Forms of Life

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Forms of Life
Barry Smith http//ifomis.org
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Scales of anatomy
Organism
Organ
Tissue
10-1 m
Cell
Organelle
10-5 m
Protein
DNA
10-9 m
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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

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FUNCTIONAL GENOMICS

• proteomics,
• reactomics,
• metabonomics,
• phenomics,
• behaviouromics,
• toxicopharmacogenomics

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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?

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Answer

• Ontology

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Google hits (as of yesterday)

• ontology philosophy 143K
• ontology engineering 145K
• ontology information systems 217K
• ontology software 252K
• ontology database 279K

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IFOMIS

• Institute for Formal Ontology
• and Medical Information Science

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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 ?

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A Linnaean Species Hierarchy
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Medical Diagnostic Hierarchy
a hierarchy in the realm of diseases
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Combining hierarchies
Organisms
Diseases
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via Dependence Relations
Organisms
Diseases
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A Window on Reality
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A Window on Reality
Organisms
Diseases
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A Window on Reality
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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

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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

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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

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Fragment of the UMLSemantic Network
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UMLS Semantic Network

• entity event
• physical conceptual
• object entity
• organism

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conceptual entity

• Organism Attribute
• Finding
• Idea or Concept
• Occupation or Discipline
• Organization
• Group
• Group Attribute
• Intellectual Product
• Language

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• 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

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Trattenbach

• is an Idea or Concept

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• 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

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Problem Confusion of concepts and entities in
reality
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Blood Pressure Ontology

• The hydraulic equation
• BP COPVR
• arterial blood pressure (BP) is directly
  proportional to the product of blood flow
  (cardiac output, CO) and peripheral vascular
  resistance (PVR).

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UMLS-Semantic Types

• blood pressure is an Organism Function,
• cardiac output is a Laboratory or Test Result or
  Diagnostic Procedure
• BP COPVR thus asserts that
• blood pressure is proportional either to a
  laboratory or test result or to a diagnostic
  procedure

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Problem Confusion of reality with our (ways of
gaining) knowledge about reality
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What are the terms of ontologies in the
ontological engineering sense

• Answer Concepts

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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

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• Trattenbach is_a class of synonymous terms

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UMLS Semantic Network

• entity
• physical conceptual
• object entity
• organism

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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)

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• fish is_a vertebrate
• enzyme is_a biologically active substance
• copulation is_a biological process

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Fragment of the UMLSemantic Network
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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

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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

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• 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

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Fragment of the UMLSemantic Network
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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.

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Belnap

• its a good thing logicians were around before
  computer scientists
• if computer scientists had got there first,
  then we wouldnt have numbers
• because arithmetic is undecidable

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• INSTANcES ARE SINGLETONS

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• 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/redundan
  cy/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

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Aristotle-Linnaeus Theory of Species and Instances
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species, genera
mammal
frog
instances
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Husserls Science of Pure Logic
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species, genera
a stands in R to something
mammal is P
a stands in R to b
instances
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species, genera
a stands in R to something
mammal is P
a stands in R to b
LAWS OF LOGIC LAWS OF ESSENCE GOVERNING
STRUCTURES/COMBINATIONS OF JUDGMENT
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The historical epistemology of the sciences

• life-world
• physics

medicine molecular biology
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Different scientific cultures/terminologies

• immunology

genetics
cell biology
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(Quine)

• an ontology is a systematic representation of
  the ontological commitments of a given scientific
  discipline, culture, commercial enterprise
• childrens ontology
• Buddhist ontology
• wine ontology

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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

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Semantic Web

• Ontology-based unification
• REDUCE EVERYTHING TO SYNTACTIC STRINGS IN SOME
  Ontology Web Language
• and STIR VIGOROUSLY
• The Crisis of Bioinformatic Sciences

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An alternative research programme for
ontologybased on philosophical principles

• Department of Biological Structure (Seattle)
• Ontek Corporation (Buffalo)
• Laboratory for Applied Ontology (Trento/Rome)

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BFO

• Basic Formal Ontology
• (counterpart of pure mathematics)

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A Network of Domain Ontologies
Basic Formal Ontology

• Material (Regional) Ontologies

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A Network of Domain Ontologies
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A Network of Domain Ontologies
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Part Three ARO The Anatomy Reference Ontology
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• Anatomy Reference Ontology
• theoretical framework surrounding the Digital
  Anatomist Foundational Model of Anatomy of
  Department of Biological Structure, University of
  Washington, Seattle

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A Linnaean Hierarchy
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at every level of granularity
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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.

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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)

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Part Four GO The Gene Ontology
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GO is three ontologies

• cellular components
• molecular functions
• biological processes
• December 16, 2003
• 1372 component terms
• 7271 function terms
• 8069 process terms

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GO product of Open Biological Ontologies
consortium

• Fungal Ontology
• Plant Ontology
• Yeast Ontology
• Disease Ontology
• ...

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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?

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GOs three ontologies
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The Cellular Component Ontology (counterpart of
anatomy)

• flagellum
• chromosome
• membrane
• cell wall
• nucleus

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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

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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

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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

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but GO built by biologists

• compare the Gene Statistic

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hemolysis

• Definition
• The cause of hemolysis

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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.

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Biological Process

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

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Each of GOs 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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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 dont
  know
• Holliday junction helicase complex
• is-a
• unlocalized

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GO0008372 cellular component unknown cellular
component unknown is-a cellular component
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Is biological classification Linnaean?
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Principle of Single Inheritance

• no class in a true (Linnaean) hierarchy should
  have more than one parent on the immediate higher
  level
• no diamonds

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Problems with multiple inheritance

• B C
• is-a1 is-a2
• A
• is-a no longer univocal

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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

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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

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extrinsic to

• extrinsic to membrane
• extrinsic to membrane part-of membrane

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GOs three ontologies are separate
biological processes
molecular functions

• No links or edges defined between them

cellular components
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Three granularities

• Molecular (for functions)
• Cellular (for components)
• Whole organism (for processes)

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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)

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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

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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

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Part Five

• Extending GO to make a full ontology by adding
  relations of dependence

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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

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Principle of Dependence

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

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Linking to external ontologies

• can also help to link together GOs own three
  separate parts

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GOs three ontologies
biological processes
molecular functions
? dependent ?
cellular components
? independent
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GOs three ontologies
organism-level biological processes
cellular processes
molecular functions
cellular components
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molecular functions
cellular processes
organism-level biological processes
molecule complexes
cellular components
organisms
part-of is dependent
on
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molecule complexes
cellular components
organisms
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molecule complexes
cellular components
organisms
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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

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• The End

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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

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Organism
Organ
Tissue
Cell
Organelle
Protein
DNA
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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?

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Answer

• Ontology

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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

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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

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Formal ontology an analogue of pure mathematics

• Can be applied to different domains

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Material ontology a kind of generalized chemistry
or zoology

• (Aristotles ontology grew out of biological
  classification)

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Aristotle
worlds first ontologist

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Worlds first ontology (from Porphyrys
Commentary on Aristotles Categories)
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Linnaean Ontology
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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

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Formal Ontology

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

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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

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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)

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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.

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Example of a Formal-Ontological Structure
A
B
C
E
D
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Ontological Structure
A
B
C
E
D
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Ontological Structure
A
B
F
C
E
D
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A Network of Domain Ontologies
Basic Formal Ontology

• Material (Regional) Ontologies

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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

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Material Ontology of Social Interaction
oblig-ation
claim
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A Window on Reality
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Universals
oblig-ation
claim
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Instances
oblig-ation
claim
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A Window on Reality
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Medical Diagnostic Hierarchy
a hierarchy in the realm of diseases
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Dependence Relations
Organisms
Diseases
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A Window on Reality
Organisms
Diseases
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A Window on Reality
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universals
mammal
frog
instances
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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

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Problem The different source vocabularies are
incompatible with each other
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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

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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

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Bad definitions

• Heptolysis def the cause of heptolysis
• Biological process def a biological goal that
  requires more than one function

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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

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correct reading of is-a

• A and B are natural kinds,
• there are times at which instances of A exist,
• 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

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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)

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Instances are elite individuals

• they are those which instantiate universals
  (entering into biological laws)

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Linnaean Ontology
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Confusion of Ontology and Epistemology

• Physical Object
• Substance
• Food Chemical Body Substance

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Confusion of Ontology and Epistemology

• Chemical
• Chemical Chemical
• Viewed Viewed
• Structurally Functionally

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

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• Chemical
• Chemical Chemical
• Viewed Viewed
• Structurally Functionally
• Inorganic Organic
  Biomedical or
• Chemical Chemical Dental
  Material

Enzyme
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Is biological classification Linnaean?
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Principle of Single Inheritance

• (rule of thumb) no class in a classificatory
  hierarchy should have more than one parent

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The Problem of Multiple Inheritance

• cars
• Buicks blue cars
• blue Buicks

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Principle of Taxonomic Levels

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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 GOs hierarchies not determinate
  because of multiple inheritance

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Principle of Exhaustiveness

• the classes on any given level should exhaust
  the domain of the classificatory hierarchy.

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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

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Problems with multiple inheritance

• B C
• is-a1
  is-a2
• A
  E
• D
• sibling is no longer determinate

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Problems with multiple inheritance

• B C
• is-a1
  is-a2
• A
  E
• D
• is_a is no longer univocal

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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

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How are universals and instances related together?
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Entities
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Entities
universals (classes, types, taxa, )
particulars (individuals, tokens, instances )
Axiom Nothing is both a universal and a
particular
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Two Kinds of Elite Entities

• classes, within the realm of universals
• instances within the realm of particulars

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Entities
classes
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Entities
classes natural, biological
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Entities
classes of objects, substances need
modified axioms for classes of functions,
processes, pathways, reactions, etc.
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Entities
classes
instances
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Classes are natural kinds

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

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Entities
classes
instances
instances
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Entities
classes
junk
junk
instances
junk
example of junk beachball-desk
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Primitive relations inst and part

• inst(Jane, human being)
• part(Janes heart, Janes body)
• A class is anything that is instantiated
• An instance as anything (any individual) that
  instantiates some class

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Entities
human
inst
Jane
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Entities
human
Janes heart part Jane
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part as a relation between individuals

• subject to the usual axioms of mereology

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Two primitive relations inst and part

• inst(Jane, human being)
• part(Janes heart, Janes body)
• A universal is anything that is instantiated
• An instance is anything (any individual) that
  instantiates some class

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Two primitive relations inst and part

• Axioms governing inst
• it holds in every case between an instance and a
  class, in that order
• 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)

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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.

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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.

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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

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if they can be cleared up at all
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Fragment of the UMLSemantic Network
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• 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

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What are universals?

• invariants in reality
• satisfying biological laws
• (there are truths about universals in biological
  textbooks)

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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)

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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

• 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
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
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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
Towards an Tri-Categorial Ontology

• of Structures, Functions and Processes

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
The Kidney From Andrew Lonie, University of
Melbourne
Your entire blood volume flows through your
kidneys every few minutes, leaving behind excess
water, solutes and waste materials
201
How does a kidney work?
Essentially a massively parallel filter composed
of 105 to 106 nephrons The nephron is the
functional unit of the kidney Each nephron is a
very convoluted, long, thin tube lined with
biochemical pumps
202
Nephron Functions
10 functional segments
15 different cell types
203
Structural and functional representation
Structural ontology Kidney Renal
architecture Tubule section/ Glomerulus Cell
ANATOMY AT DIFFERENT LEVELS OF GRANULARITY
process ontology (molecular, cellular,
organ-level )
204
UMLS Semantic Network

• entity event
• physical conceptual
• object entity
• organism

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
RUMLS Semantic Network

• entity event
• structures functions processes

207
GOs 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
RUMLS Semantic Network

• entity event
• structures functions processes

209
Functional Genomics

• What does Functional mean?

210
The Problem

• The tumor developed in Johns lung over 25 years

211
The Problem

• ____ developed in _____ over 25 years
• process

212
The Problem

• The tumor developed in the lung over 25 years
• substances
• things
• objects
• continuants

213
The Problem

• The tumor developed in Johns lung over 25 years
• PARTHOOD NOT DETERMINATE

214
The Problem

• The tumor developed in the lung over 25 years
• substances
• GLUING THESE TOGETHER YIELDS ONTOLOGICAL MONSTERS

215
Substances and processes exist in time in
different ways
substance
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
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
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
Fourdimensionalism (the SPAN perspective) is
right in everything it says

• But incomplete

220
Need for Two Orthogonal, Complementary
Perspectives
SNAP and SPAN
221
Snapshot Video ontology
ontology
substance
222
SNAP and SPAN

• stocks and flows
• commodities and services
• product and process
• anatomy and physiology

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
You are a substance

• Your life is a process
• You are 3-dimensional
• Your life is 4-dimensional

225
Many SNAP Ontologies
t3
t2
t1
here time exists outside the ontology, as an
index or time-stamp
226
each SNAPi section through reality
227
mereology works without restriction (parthood is
everywhere determinate) in every SNAPi ontology
228
Three kinds of SNAP entities

1. SNAP Independent Entities (you and me)
2. SNAP Dependent Entities
3. Spatial regions

229
SNAP dependent entities

• States, powers, qualities, functions,
  dispositions, plans, shapes, liabilities,
  propensities

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

• relational SNAP dependent entities

stand in relations of one-sided dependence to a
plurality of substances simultaneously
one-sided dependence
232
A Window on Reality
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
SNAP Entities existing in toto at a time
http//ontology.buffalo.edu/bfo
235
The SPAN Ontology
236
The SPAN ontology
here time exists as part of the domain of the
ontology
237
mereology works without restriction everywhere
here
238
mereology works without restriction everywhere
here
239
Processes, too, are dependent on substances

• One-place vs. relational processes
• One-place processes
• your getting warmer
• your getting hungrier

240
Relational processes

• kissings, thumpings, conversations,
• dancings, promisings, infectings, bindings
• join their carriers together into collectives of
  greater or lesser duration

241
SPAN Entities extended in time
http//ontology.buffalo.edu/bfo
242
Two kinds of SPAN entities

1. Processes (including events process-boundaries,
   settings)
2. Spatio-temporal regions

243
How do you know whether an entity is SNAP or SPAN?
244
problem cases

• forest fire
• hurricane Maria
• traffic jam
• ocean wave
• disease
• anthrax epidemic

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
A disease

• The course/history of a disease

247
The Epidemic (SNAP)

• The Spread of an Epidemic (SPAN)

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
The Tri-Categorial Ontology

• SNAP SPAN
• structures functions processes
• independent dependent
• continants continuants

250
The Tri-Categorial Ontology

• continuants occurrents
• structures functions processes
• independent dependent
• continants continuants

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
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
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
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
Functions can exist even when they are not being
realized
256
Processes (realizations) are causal-energetic

• 
  
• 
  
• time

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

• 
  
• 
  time

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
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
Biological functions are always constituent
functions

• If X has a biological function then there is some
  Y of which X is a part and Xs functioning is in
  the service of / for the benefit of Y

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
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
Does this sense of function correspond to the
way biologists talk?
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
Health Disease Illness

• Diseased organ organ predisposed to malfunction
• Its functioning is defective

266
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267
Part Four Definitions of Health

• World Health Organization
• Health is the state of psychological and
  physical well-being of humans

268
Biostatistical TheoryChristopher Boorse

• Health is conformity to normal species design (as
  statistically determined).
• Abnormally healthy people are therefore in fact
  sick (?)

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 persons body
  or mind that tends to cause ill health in the
  bearer.

270
The Ordinary Action TheoryK.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
The Abnormality TheoryLawrie 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 circumstancessomething does a person
  harm if it makes the person less able to live a
  good or worthwhile life.

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
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
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
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
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
Diseases are both historical and quasi-Platonic

• 
  
• 
  time

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
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
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
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282
Outside the core

• are process shapes which are not instances of
  functioning at all

283
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284
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285
Normal functioning

• functioning (realizing a four-dimensional
  shape) at or close to the prototype

286
Prototypes
good functioning
287
Prototypes
reasonable functioning
288
Poor functioning
poor functioning
289
Malfunctioning
malfunctioning
290
Death?
not functioning at all
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
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
Millikan backward looking, focused on whole
species

• This account forward looking, focused on single
  organism
• X has a function (1) Xs functioning is
  beneficial to the organism of which X is a part

294
Boorses Internal Impairment Theory

• Disease is an internal state which is an
  impairment or limitation of normal functional
  ability.

295
Disease
296
Disease remoteness from prototypical functioning
disease
297
Disease remoteness from prototypical functioning
1 not functioning at all 2 malfunctioning 3
functioning poorly
1 2 3
disease
298
Not functioning at all

• death modulo
• criticality of the system involved

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
Immediate parts of the organism are more critical
301
Bodily Systems
digestive
respiratory
circulatory
immune
skeletal
musculatory
302
ENDOCRINE SYSTEM
303
KIDNEY
304
How does a kidney work?
NEPHRON
305
Nephron Functions
FUNCTIONAL SEGMENTS
306
Organism
Organ
Tissue
Cell
Organelle
Protein
DNA
307
Coda on Normal

• Normal functioning of the pancreas
• Normal functioning of the sexual organs
• On the several senses of normal in biology

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
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

• The End