1 Forms of Life Barry Smith

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3 DNA m

4 DNA Protein Organelle Cell Tissue Organ Organism m m m

5 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

6 DNA Protein Organelle Cell Tissue Organ Organism m m m

7 DNA Protein Organelle Cell Tissue Organ Organism m m m The method of annotations

8 FUNCTIONAL GENOMICS proteomics, reactomics, metabonomics, phenomics, behaviouromics, toxicopharmacogenomics …

9 The incompatibilities between different scientific cultures and terminologies immunology genetics cell biology

10 have resurrected the problem of the unity of science in a new guise: 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 … when each (chemical, pathological, immunological, toxicological) information system uses its own classifications how can we overcome the incompatibilities which become apparent when data from distinct sources are combined?

12 Answer: “Ontology”

13 = building software artefacts standardized classification systems/ controlled vocabularies so that data from one source should be expressed in a language which makes it compatible with data from every other source

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

15 IFOMIS Institute for Formal Ontology and Medical Information Science

16 The Curse of Computer Science The Only Rule: Write programs which run. Sacrifice expressivity and reasoning power Embrace a crassly simplified view of reality Result: Bioinformatics becomes a manipulation of ‘strings’ (a species of cabbalistics) Pattern recognition (googling) replaces logical inference

17 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”

18 Taxonomies

19 A Linnaean Species Hierarchy

20 (Small) Disease Hierarchy

21 Combining hierarchies Organisms Diseases

22 via Dependence Relations Organisms Diseases

23 A Window on Reality

24 A Window on Reality Organisms Diseases

25 A Window on Reality

26 Unified Medical Language System (UMLS) contains information about over 1 million biomedical concepts and 2.8 million concept names from more than 100 controlled vocabularies and classifications (built by US Federal Government Linguists)

27 to find new drugs …

28 UMLS Source Vocabularies ICD International Classification of Diseases MeSH – Medical Subject Headings GO – Gene Ontology FMA – Foundational Model of Anatomy …

29 To reap the benefits of standardization we need to make ONE SYSTEM out of these many different terminologies = UMLS “Semantic Network” nearest thing to an “ontology” in the UMLS

30 Fragment of the UMLSemantic Network

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33 UMLS Semantic Network entity event physical conceptual object entity organism

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

35 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

36 Trattenbach is an Idea or Concept

37 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

38 Problem: Confusion of concepts and entities in reality

39 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).

40 UMLS-Semantic Types: blood pressure is an Organism Function, cardiac output is a Laboratory or Test Result or Diagnostic Procedure

41 UMLS-Semantic Types: BP = CO*PVR thus asserts that blood pressure is proportional either to a laboratory or test result or to a diagnostic procedure

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

43 What are concepts?

44 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

45 UMLS Semantic Network entity physical conceptual object entity organism

46 UMLS Semantic Network entity physical conceptual object entity organism substance

47 Confusion of Ontology and Epistemology Physical Object Substance Food Chemical Body Substance

48 Confusion of Ontology and Epistemology Chemical Viewed Structurally Functionally

49 Chemical Viewed Structurally Functionally Inorganic Organic Enzyme Biomedical or Chemical Chemical Dental Material

50 UMLS Semantic Network entity physical conceptual object entity organism is_a

51 Semantic Network 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)

52 fish is_a vertebrate copulation is_a biological process both testes is_a testis both uteri is_a uteris

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55 How can concepts figure as relata of these relations? Or of: 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.

56 How can a set of synonymous terms serve as a receptacle for fluids or other substances? How can sets of synonymous terms stand in relations such as affects or causes?

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58 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

59 The Curse of Linguistics Work on biomedical ontologies grew out of work on medical dictionaries and nomenclatures This led to the assumption that all that need be said about classes can be said without appeal to time or to instances in reality. Ontology is about meanings/terms/strings

60 An alternative research programme for ontology based on philosophical principles Terms in bio-ontologies refer not to ‘concepts’ but to universals in reality

61 IFOMIS methodology embraced by: Department of Biological Structure (Seattle) Laboratories for Applied Ontology (Trento/Rome/Turin) Ontology Works (Baltimore) The Gene Ontology Consortium

62 Already reformed Foundational Model of Anatomy Anatomy Reference Ontology Physiology Reference Ontology Pathology Reference Ontology

63 Aristotle-Linnaeus Theory of Species and Canonical Instances

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66 Entities

67 Entities universals (classes, types, taxa, …) particulars (individuals, tokens, instances)

68 Two Kinds of Elite Entities natural kinds, within the realm of universals

69 Entities natural kinds

70 Canonical instances within the realm of individuals = those individuals which 1. instantiate universals (entering into biological laws) 2. are prototypical  Canonical Anatomy: no Siamese twins, no six-fingered giants, no amputation stumps, …

71 Entities natural kinds instances

72 Entities natural kinds instances junk example of junk particulars: desk-mountain

73 Entities human Jane inst

74 Entities human Jane’s heart part Jane

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

76 part_of as a relation between universals A part_of B = def given any x, if inst(x, A) then there is some y such that inst(y, B) and part(x, y) human testis part_of human being, But not: heart part_of human being.

77 To represent ontological relations we need to take instances into account To say A part_of B is not to say anything about Bs’ need for As as parts

78 The Gene Ontology a controlled vocabulary for annotations of genes and gene products

79 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?

80 GO has three ontologies molecular functions cellular components biological processes

81 GO astonishingly influential used by all major species genome projects used by all major pharmacological research groups used by all major bioinformatics research groups

82 GO part of the Open Biological Ontologies consortium Fungal Ontology Plant Ontology Yeast Ontology Disease Ontology Mouse Anatomy Ontology Cell Ontology Sequence Ontology Relations Ontology

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)

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85 cellular components molecular functions biological processes 1372 component terms 7271 function terms 8069 process terms

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

87 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

88 Biological Process Ontology glycolysis copulation death An ontology of occurrents on the level of granularity of cells, organs and whole organisms

89 GO built by biologists free of the Curse of Linguistics free of the Curse of Computer Science

90 but problems still remain menopause part_of aging aging part_of death menopause part_of death

91 heptolysis Definition The causes of heptolysis …

92 regulation of sleep part_of sleep extrinsic to membrane part_of membrane

93 GO uses only two relations is_a and part_of

94 hence GO has only sentences of the forms 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’:

95 Holliday junction helicase complex is-a unlocalized cellular component unknown is-a cellular component

96 Old GO definition of part_of A part_of B = def A can be part of B

97 New GO definition of part_of A part_of B = def given any x, if inst(x, A) then there is some y such that inst(y, B) and part(x, y)

98 Clarifying GO’s ontology of ‘function’ What does ‘function’ mean in expressions like ‘functional genomics’? Function = what a gene or gene product does

99 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

100 Molecular Function GO’s Old Definition: An activity or task performed by a gene product.

101 Problem: Not every activity (process) in an organism is the exercise of a function – there are junk processes – mal functionings –accidents

102 What does function mean?

103 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

104 Nephron Functions 10 functional segments 15 different cell types

105 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

106 Functions fantastically hierarchically organised mutual complementation contextual dependence

107 What does “Function” mean? First hypothesis: if instances of A have (biological) functions then As are instance-level parts of organisms Biological functions are constituent functions Ingvar Johansson

108 Structures, objects, continuants which have functions Processes which realize functions Functions which become realized through those special sorts of processes we call functionings

109 A Tri-Categorial Ontology Continuants Occurrents structures functions processes = independent = dependent continants continuants

110 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

111 Functions can exist even when they are not being realized Sperm … Uteri …

112 Functionings are elite entities in the realm of processes: they are processes which 1. instantiate universals (entering into biological laws) 2. are prototypical

113 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

114 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

115 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

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

117 Functioning = functioning (realizing a four-dimensional shape) at or close to the prototype

118 Prototypes functioning

119 poor functioning

120 malfunctioning

121 not functioning at all

122 Functionings are elite entities in the realm of processes: they are processes which 1. instantiate universals (entering into biological laws) 2. are prototypical

123 But is there something more? Is it the function of an oncogene: to cause cancer ? NO: Oncogenes were in every case proto- oncogenes with proper functions of their own they become oncogenes because of bad (non-canonical) environments

124 (Biological) functions are always beneficial to the host organism If Y has a function F, then there is some organism O of which Y is a part and Y’s performing F is beneficial for O/for O’s survival (forward looking view)

125 beneficial =are (in normal circumstances) such as to sustain the organism in existence (?)

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

127 Millikan’s ‘proper function’ F is the function of Y means: 1) Y performs F and 2) Y exists because its predecessors’ performing F is responsible for my existing Functions = dispositions which were selected for biologically (backward looking view)

128 You have a heart because your parents had hearts …

129 Functional Genomics = study of what genes contributed in order to give rise to organism parts acting in certain ways

130 If Y has a function then there is some organism O of which Y is a part and similar ancestral functioning is responsible for X’s existence

131 Two communities of biologists Theoretical vs clinical

132 Theoretical sense of ‘function’ biological structures ‘gain function’ (= being switched on) even where their functioning is not beneficial So that not all functions associated with malfunctionings? Being-in-function – mass nounc

133 Clinical sense of ‘function’ The heart has the function: to pump blood (count noun): means: it pumps blood prototypically and it is good for you that it does so This gives us an account of what clinical medicine is for = to eliminate malfunctioning by fixing broken body parts

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

135 The beneficiality view also gives us an account of a number of notions intimately related to the notion of function malfunction regulation substitution promotion inhibition

136 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

137 One disadvantage of both views How cope with those parts of your body which function in such a way as to bring about aging and death?

138 Against Millikan: Those of your body parts responsible for processes involved in aging and death precisely do not exist because their predecessors’ having performed these same processes is responsible for your existing (at least not directly)

139 The solution Canonical anatomy = anatomy of the canonical human being in the canonical anatomical position (no amputation stumps …)

140 To understand function we need to postulate Canonical physiology = physiology of the canonical human being leading the canonical life canonical embryological development canonical growth canonical aging canonical death

141 Revised definition of function If Y has a function F, then there is some organism O of which Y is a canonical anatomical part and Y’s performing F contributes to O’s canonical physiology

142 Functional genomics = study of what the genes contribute to the canonical physiology of the organism Functional genomics would then be dependent on embryology, physiology, theory of growth and aging, for each species.

143 The two-faced character of functional genomics Teleology vs. actual practice

144 DNA Protein Organelle Cell Tissue Organ Organism m m m

145 The End