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Forms of Life
Barry Smith
http://ifomis.org
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10-9 m
DNA
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Organism
Organ
10-1 m
Tissue
Cell
10-5 m
Organelle
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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Organism
Organ
10-1 m
Tissue
Cell
10-5 m
Organelle
Protein
DNA
10-9 m
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Organism
The method of
annotations
Organ
10-1 m
Tissue
Cell
10-5 m
Organelle
Protein
DNA
10-9 m
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FUNCTIONAL GENOMICS
proteomics,
reactomics,
metabonomics,
phenomics,
behaviouromics,
toxicopharmacogenomics
…
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The incompatibilities between different
scientific cultures and terminologies
immunology
genetics
cell biology
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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?
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… 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?
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Answer:
“Ontology”
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= 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
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Google hits (as of yesterday)
ontology + philosophy
ontology + engineering
ontology + information systems
ontology + software
ontology + database
143K
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217K
252K
279K
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IFOMIS
Institute for Formal Ontology
and Medical Information
Science
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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
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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”
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Taxonomies
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A Linnaean Species Hierarchy
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(Small) Disease Hierarchy
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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
Diseases
Organisms
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A Window on Reality
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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)
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to find new drugs …
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UMLS Source Vocabularies
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
these many different terminologies
=
UMLS “Semantic Network”
nearest thing to an “ontology” in the UMLS
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Fragment of the UMLSemantic Network
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UMLS Semantic Network
entity
physical
object
event
conceptual
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 = CO*PVR
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
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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
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Problem: Confusion of reality with
our (ways of gaining) knowledge
about reality
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What are concepts?
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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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UMLS Semantic Network
entity
physical
object
conceptual
entity
organism
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UMLS Semantic Network
entity
physical
object
organism
conceptual
entity
substance
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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
Viewed
Structurally
Chemical
Viewed
Functionally
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Chemical
Chemical
Viewed
Structurally
Inorganic Organic
Chemical Chemical
Chemical
Viewed
Functionally
Enzyme
Biomedical or
Dental Material
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UMLS Semantic Network
entity
is_a
physical
object
conceptual
entity
organism
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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)
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fish is_a vertebrate
copulation is_a biological process
both testes is_a testis
both uteri is_a uteris
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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.
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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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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
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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
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An alternative research programme
for ontology
based on philosophical principles
Terms in bio-ontologies refer not
to ‘concepts’
but to universals in reality
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IFOMIS methodology embraced by:
Department of Biological Structure
(Seattle)
Laboratories for Applied Ontology
(Trento/Rome/Turin)
Ontology Works (Baltimore)
The Gene Ontology Consortium
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Already reformed
Foundational Model of Anatomy
Anatomy Reference Ontology
Physiology Reference Ontology
Pathology Reference Ontology
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Aristotle-Linnaeus Theory of
Species and Canonical Instances
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Anatomical Entity
Physical
Anatomical Entity
Conceptual
Anatomical Entity
-is a-
Anatomical
Relationship
Material Physical
Anatomical Entity
Body
Substance
Anatomical
Space
Anatomical
Structure
Biological
Macromolecule
Cell
Part
Non-material Physical
Anatomical Entity
Cell
Tissue
Organ
Organ
Part
Organ
System
Body
Part
Human
Body
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Body
Substance
Biological
Macromolecule
Cell
Part
Anatomical
Space
Anatomical
Structure
Cell
Tissue
Organ
Organ
Part
Organ
System
Body
Part
Human
Body
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Entities
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Entities
universals (classes, types, taxa, …)
particulars (individuals, tokens, instances)
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Two Kinds of Elite Entities
natural kinds, within the realm of
universals
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Entities
natural kinds
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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, …
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Entities
natural kinds
instances
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Entities
natural kinds
junk
junk
instances
junk
example of junk particulars: desk-mountain
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Entities
human
inst
Jane
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Entities
human
Jane’s heart part Jane
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part as a relation between
individuals
subject to the usual axioms of
mereology
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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.
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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
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The Gene Ontology
a controlled vocabulary for
annotations of genes and gene
products
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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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GO has three ontologies
biological
processes
molecular
functions
cellular
components
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GO astonishingly influential
used by all major species genome projects
used by all major pharmacological research
groups
used by all major bioinformatics research
groups
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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
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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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cellular components
molecular functions
biological processes
1372 component terms
7271 function terms
8069 process terms
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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
glycolysis
copulation
death
An ontology of occurrents on the level of
granularity of cells, organs and whole
organisms
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GO built by biologists
free of the Curse of Linguistics
free of the Curse of Computer
Science
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but problems still remain
menopause part_of aging
aging part_of death
menopause part_of death
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heptolysis
Definition
The causes of heptolysis …
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regulation of sleep part_of sleep
extrinsic to membrane part_of membrane
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GO uses only two relations
is_a and part_of
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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’:
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Holliday junction helicase complex
is-a
unlocalized
cellular component unknown is-a
cellular component
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Old GO definition of part_of
A part_of B =def A can be part of B
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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)
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Clarifying GO’s ontology of ‘function’
What does ‘function’ mean in expressions
like ‘functional genomics’?
Function = what a gene or gene product
does
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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
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Molecular Function
GO’s Old Definition:
An activity or task performed by a gene
product.
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Problem:
Not every activity (process) in an organism
is the exercise of a function – there are
junk processes
mal functionings
– accidents
–
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What does function mean?
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The Kidney
What do the kidneys do?
From Andrew Lonie
Your entire blood
volume flows through
your kidneys every
few minutes, leaving
behind excess water,
solutes and waste
materials
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Nephron Functions
10 functional segments
15 different cell types
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massively
How doesEssentially
a kidney awork?
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
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Functions fantastically
hierarchically organised
mutual complementation
contextual dependence
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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
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Structures, objects, continuants which have
functions
Processes which realize functions
Functions which become realized through
those special sorts of processes we call
functionings
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A Tri-Categorial Ontology
Continuants
structures
functions
= independent
continants
= dependent
continuants
Occurrents
processes
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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
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Functions can exist even when
they are not being realized
Sperm …
Uteri …
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Functionings are elite entities in the
realm of processes:
they are processes which
1. instantiate universals (entering
into biological laws)
2. are prototypical
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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
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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
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For each function
there is an associated family of (fourdimensional) 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
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Outside the core
are process shapes which are not instances
of functioning at all
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Functioning
= functioning (realizing a four-dimensional
shape) at or close to the prototype
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Prototypes
functioning
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poor
functioning
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malfunctioning
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not
functioning
at all
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Functionings are elite entities in the
realm of processes:
they are processes which
1. instantiate universals (entering
into biological laws)
2. are prototypical
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But is there something more?
Is it the function of an oncogene: to cause
cancer ?
NO: Oncogenes were in every case protooncogenes with proper functions of their
own
they become oncogenes because of bad
(non-canonical) environments
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(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)
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beneficial
= are (in normal circumstances) such as to
sustain the organism in existence (?)
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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)
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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)
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You have a heart because your
parents had hearts …
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Functional Genomics
= study of what genes contributed in order to
give rise to organism parts acting in
certain ways
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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
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Two communities of biologists
Theoretical vs clinical
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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
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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
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Boorse’s Internal Impairment
Theory of Disease
Disease is an internal state which is an
impairment or limitation of normal
functional ability.
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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
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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
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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?
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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)
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The solution
Canonical anatomy = anatomy of the
canonical human being in the canonical
anatomical position (no amputation
stumps …)
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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
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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
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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.
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The two-faced character of
functional genomics
Teleology vs. actual practice
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Organism
Organ
10-1 m
Tissue
Cell
10-5 m
Organelle
Protein
DNA
10-9 m
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The End
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