1 The Canonical Life Barry Smith

2 Ontology (Phil.) = the science of the types of objects, qualities, proesses, events, funktions, environments, relations... in all spheres of reality

3 Google hits (in millions) ontology 24.0 ontology + philosophy 4.6 ontology + information science 7.4 ontology + database 11.1

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5 ontology (computer science) (roughly) the construction of standardized classification systems designed to make databases compatible with each other

6 National Center for Biomedical Ontology $18.8 mill. NIH Roadmap Center Stanford Medical Informatics University of San Francisco Medical Center Berkeley Drosophila Genome Project Cambridge University Department of Genetics The Mayo Clinic University at Buffalo Department of Philosophy

7 From chromosome to disease

8 genomics transcriptomics proteomics reactomics metabonomics phenomics behavioromics connectomics toxicopharmacogenomics bibliomics … legacy of Human Genome Project

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10 we need to know where in the body we need to know what kind of disease process = we need ontologies we need semantic annotation of data

11 how create broad-coverage semantic annotation systems for biomedicine? covering: in vitro biological phenomena model organisms humans

12 OBO Foundry Project ontology developers in the life sciences have agreed in advance to accept a growing set of best practices in ontology development to ensure interoperability and additivity of annotations

13 OntologyScopeURLCustodians Cell Ontology (CL) cell types from prokaryotes to mammals obo.sourceforge.net/cgi- bin/detail.cgi?cell Jonathan Bard, Michael Ashburner, Oliver Hofman Chemical Entities of Bio- logical Interest (ChEBI) molecular entitiesebi.ac.uk/chebi Paula Dematos, Rafael Alcantara Common Anatomy Refer- ence Ontology (CARO) anatomical structures in human and model organisms (under development) Melissa Haendel, Terry Hayamizu, Cornelius Rosse, David Sutherland, Foundational Model of Anatomy (FMA) structure of the human body fma.biostr.washington. edu JLV Mejino Jr., Cornelius Rosse Functional Genomics Investigation Ontology (FuGO) design, protocol, data instrumentation, and analysis fugo.sf.netFuGO Working Group Gene Ontology (GO) cellular components, molecular functions, biological processes Ontology Consortium Phenotypic Quality Ontology (PaTO) qualities of anatomical structures obo.sourceforge.net/cgi -bin/ detail.cgi? attribute_and_value Michael Ashburner, Suzanna Lewis, Georgios Gkoutos Protein Ontology (PrO) protein types and modifications (under development)Protein Ontology Consortium Relation Ontology (RO) relationsobo.sf.net/relationshipBarry Smith, Chris Mungall RNA Ontology (RnaO) three-dimensional RNA structures (under development)RNA Ontology Consortium Sequence Ontology (SO) properties and features of nucleic sequences song.sf.netKaren Eilbeck

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16 When a gene is identified three 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?

17 where in the cell ? what kind of biological process ? what kind of molecular function?

18 GO’s three ontologies molecular functions cellular components biological processes

19 Three granularities: Cellular (for components) Molecular (for functions) Organ + organism (for processes)

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21 The Granularity Gulf most existing data-sources are of fixed, single granularity many (all?) clinical phenomena cross granularities

22 GO’s three ontologies molecular function cellular component biological process

23 GO’s three ontologies molecular function cellular component organism- level biological process cellular process

24 molecular function molecule cellular process cellular component organism- level biological process organism Normalization of Granular Levels

25 need to separate function from activity

26 molecule cellular component molecular function cellular function organism- level biological function organism molecular process cellular process organism- level biological process

27 types of process stochastic processes (Brownian motion of blood cells) accidents (heart penetrated by bullet) functionings (heart pumping) (elite processes) side-effects (heart beating) malfunctionings...

28 molecule cellular component molecular function cellular function organism- level biological function organism molecular process cellular process organism- level biological process functioning

29 molecular function cellular function organism- level biological function molecular process cellular process organism- level process functionings The new age of teleology

30 What does “function” mean? an entity has a biological function if and only if it is part of an organism and has a disposition to act reliably in such a way as to contribute to the organism’s survival the function is this disposition

31 Problem of aging and death are their parts of the organism involved in bringing about aging processes? is this their function?

32 Problem of reproductive organs an entity has a biological function if and only if it is part of an organism and has a disposition to act reliably in such a way as to contribute to the organism’s survival

33 Problem of reproductive organs an entity has a biological function if and only if it is part of an organism and has a disposition to act reliably in such a way as to contribute to a group’s survival

34 Problem of reproductive organs an entity has a biological function if and only if it is part of an organism and has a disposition to act reliably in such a way as to contribute to genes’ survival

35 Functions are organized in a modular hierarchy The function of each functional part is: to contribute to the functioning of the whole we need to understand ‘function’ in relation to the actual environing whole of the part in question

36 What do the kidneys do? The function of the kidney is to purify blood

37 How does a kidney work? The nephron is the cardinal functional unit of the kidney

38 Nephron Functions 10 functional segments 15 different cell types

39 Challenge Can we provide an account of the functions of sexual organs within this framework an entity has a biological function if and only if it is part of an organism and has a disposition to act reliably in such a way as to contribute to the organism’s survival

40 Function is what gives rise to normal activity But: that sperm function (to penetrate the ovum) is rare

41 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

42 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

43 Functions and Prototypes In its functioning, a heart creates a four- dimensional process shape. Good hearts create other process shapes than sick hearts do.

44 Prototypes functioning

45 poor functioning

46 malfunctioning

47 not functioning at all

48 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

49 What clinical medicine is for to eliminate malfunctioning by fixing broken body parts (or to prevent the appearance of malfunctioning by intervening e.g. at the molecular level)

50 What is health Boorse: the state of an organism is theoretically healthy, i.e., free from disease, in so far as its mode of functioning conforms to the natural design of that kind of organism = all its functional parts function in such a way as to promote survival and reproduction

51 Problems with Boorse’s view 1. Survival and reproduction may conflict 2. There may be parts of the organism whose function is to bring about aging and death 3. Not every malfunction is a disease, only those which contribute to what we count as illness

52 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

53 Hypothesis: there are no ‘bad’ functions It is not the function of an oncogene to cause cancer Oncogenes were in every case proto- oncogenes with functions of their own They become oncogenes because of bad (non-prototypical) environments

54 Is there an exception for molecular functions? Does this apply only to functions on biological levels of granularity (= levels of granularity coarser than the molecule) ? If pathology is the deviation from (normal) functioning, does it make sense to talk of a pathological molecule? (Pathologically functioning molecule vs. pathologically structured molecule)

55 Is there an exception for molecular functions? A molecular function is a propensity of a gene product instance to perform actions on the molecular level of granularity. Hypothesis 1: these actions must be reliably such as to contribute to biological processes. Hypothesis 2: these actions must be reliably such as to contribute to the organism’s realization of the canonical life plan for an organism of that type.

56 The Gene Ontology is a canonical ontology – it represents only what is normal in the realm of (molecular) functioning = what pertains to normal (‘wild type’) organisms (in all species)

57 The GO is a canonical representation “The Gene Ontology is a computational representation of the ways in which gene products normally function in the biological realm” Nucl. Acids Res. 2006: 34.

58 The GO is a canonical representation “The Gene Ontology is a computational representation of the ways in which gene products normally function in the biological realm” Nucl. Acids Res. 2006: 34.

59 molecule cellular component molecular function cellular function organism- level biological function organism molecular process cellular process organism- level process functionings everything here is typical

60 OntologyScopeURLCustodians Cell Ontology (CL) cell types from prokaryotes to mammals obo.sourceforge.net/cgi- bin/detail.cgi?cell Jonathan Bard, Michael Ashburner, Oliver Hofman Chemical Entities of Bio- logical Interest (ChEBI) molecular entitiesebi.ac.uk/chebi Paula Dematos, Rafael Alcantara Common Anatomy Refer- ence Ontology (CARO) anatomical structures in human and model organisms (under development) Melissa Haendel, Terry Hayamizu, Cornelius Rosse, David Sutherland, Foundational Model of Anatomy (FMA) structure of the human body fma.biostr.washington. edu JLV Mejino Jr., Cornelius Rosse Functional Genomics Investigation Ontology (FuGO) design, protocol, data instrumentation, and analysis fugo.sf.netFuGO Working Group Gene Ontology (GO) cellular components, molecular functions, biological processes Ontology Consortium Phenotypic Quality Ontology (PaTO) qualities of anatomical structures obo.sourceforge.net/cgi -bin/ detail.cgi? attribute_and_value Michael Ashburner, Suzanna Lewis, Georgios Gkoutos Protein Ontology (PrO) protein types and modifications (under development)Protein Ontology Consortium Relation Ontology (RO) relationsobo.sf.net/relationshipBarry Smith, Chris Mungall RNA Ontology (RnaO) three-dimensional RNA structures (under development)RNA Ontology Consortium Sequence Ontology (SO) properties and features of nucleic sequences song.sf.netKaren Eilbeck

61 The Foundational Model of Anatomy is a canonical representation = a representation of types and relations between types deduced from the qualitative observations of the normal human body, which have been refined and sanctioned by successive generations of anatomists and presented in textbooks and atlases of structural anatomy.

62 FMA recognizes also variant anatomical structures (e.g. coronary arteries or bronchopulmonary segments which deviate from the canonical anatomical pattern of organization)

63 A solution Canonical anatomy = anatomy of the canonical human being in the canonical anatomical position (no amputation stumps, no effects of steroids, …) For each type of organism there is a canonical Bauplan, but there is also a canonical life plan (canonical life Gestalt)

64 Model organisms you can buy a mouse with the prototypical mouse Bauplan according to a precise genetical specification

65 Canonical lifeplan = the physiological counterpart of canonical anatomy

66 the canonical life (plan) birth infancy teenagerdom early adulthood maturity late adulthood death

67 What does “function” mean? an entity has a biological function if and only if it is part of an organism and has a disposition to act reliably in such a way as to contribute to the organism’s survival the function is this disposition

68 Improved version an entity has a biological function if and only if it is part of an organism and has a disposition to act reliably in such a way as to contribute to the organism’s realization of the canonical life plan for an organism of that type

69 This canonical life plan might include canonical embryological development canonical growth canonical reproduction canonical aging canonical death

70 For all animals the canonical life Gestalt includes: canonical embryological development canonical growth canonical reproduction canonical aging canonical death

71 For non-human organisms the canonical life Gestalt is primarily canonical physiology

72 spontaneity society culture technology For a human being the canonical life Gestalt includes: birth infancy teenagerdom early adulthood maturity late adulthood death

73 canonical life Gestalten + variant life Gestalten (vegetarians, lesbians) + pathological life Gestalten (serial murderers)

74 What would the life of a wild type human being involve? Reproduction... Aging...

75 Just as there are 2 x n canonical Baupläne for human beings (male and female at n successive stages) so there may be different canonical life plans for different types of human beings if so, what are the different types?

76 Is talk of ‘life plan’ descriptive or prescriptive If prescriptive we can use it as a benchmark e.g. to measure the success of different policies Use it as a measure of flourishing Relevance to debates about endangered species Relevance to debates about ‘what is a life worth living?’

77 What is life?

78 What is a canonical environment? What is a canonical family?

79 As You Like It, II.vii Jacques: All the world's a stage, And all the men and women merely players: They have their exits and their entrances; And one man in his time plays many parts, His acts being seven ages. At first the infant, Mewling and puking in the nurse's arms. And then the whining school-boy, with his satchel, And shining morning face, creeping like snail Unwillingly to school. And then the lover Sighing like furnace, with a woeful ballad Made to his mistress' eyebrow. Then a soldier, Full of strange oaths, and bearded like the pard, Jealous in honour, sudden and quick in quarrel, Seeking the bubble reputation Even in the cannon's mouth. And then the justice, In fair round belly with good capon lin'd, With eyes severe, and beard of formal cut, Full of wise saws and modern instances; And so he plays his part. The sixth age shifts Into the lean and slipper'd pantaloon, With spectacles on nose and pouch on side, His youthful hose well sav'd a world too wide For his shrunk shank; and his big manly voice, Turning again toward childish treble, pipes And whistles in his sound. Last scene of all, That ends this strange eventful history, Is second childishness and mere oblivion, Sans teeth, sans eyes, sans taste, sans everything.

80 What does every human canonical life involve 9 months of development later acquisition of consciousness, language... cycles of waking, sleeping; eating and not eating... death

81 FirstGov Life Events Taxonomy

82 FamilyWorkMoney Adoption Aging Birth Child care Death Disability Divorce Domestic Violence Driving Elder Care Empty Nesting Health Illness Kids Marriage Parenting Retirement Schooling Teenagers Travelling Employment Injury Job Seeking Re-employment Small Business Self-employment Telecommuting Unemployment Volunteering Workplace Violence Bankruptcy Budgeting Charitable Contributions College Credit Disasters Home Improvement Home Purchase Home Selling Insurance Investing IRS Audit Lawsuits Mortgage Property Renting Saving Taxes Trusts Wills

83 Infancy has six states quiet sleep and active sleep quiet waking, and active waking fussing and crying and reflexes such as: crying sucking suckling grasping

84 Toddler Early Childhood Childhood Adolescence Early Adulthood Middle age Old age GERONTOLOGY Death

85 Different perspectives on the canonical life Aristotle: the golden mean Catholic: no contraception, no sin Evolutionary psychology: life in the African savannah Roger Barker: behavior settings Clinical medicine: goal to bring patient back in the direction of a canonical life Cryonics view: ‘life’ is defined entirely conventionally Transhumanism

86 The organizing principle of complex living systems Iberall, A. S. and McCulloch, W. S. The organizing principle of complex living systems. Journal of Basic Engineering June As a suitable engineering definition, we may provisionally define a life-like system as any compact system containing an order and distribution of sustaining nonlinear limit cycle oscillators, and a related system of algorithmic guide mechanisms, that is capable of regulating its interior conditions for a considerable range of ambient environmental conditions so as to permit its own satisfactory preservative operation; that is capable of performing these preservative functions for a long period of time commensurate with the “life” of its mechanical-physical-chemical elements; and that is capable of recreating its own internal systems, or being recreated, out of materials and equipment at hand in the ecological milieu. An essential characteristic of a living system is its marginal instability. Its principal dynamic properties are that it hungers, feeds, and can move or creep so that it can continue to hunger, feed, and move or creep. At the right unfolding time, it couples and reproduces so that the newly formed unit can hunger, feed and move about. Both the external and internal environment constantly present the organism with an impulsive (vicissitudinous) input against a background of the slowly searched, changing milieu. As a result, the motor systems of the organism are plunged into intermittent search modes to satisfy all of its hungers.

87 Iberall and McCulloch 20 action modes: Action Modes % of time Sleeps 30 Eats5 Drinks1 Voids1 Sexes3 Works 25 Rests (no motor activity, indifferent internal sensory flux)3 Talks5 Attends (indifferent motor activity, involved sensory activity)4 Motor practices (runs, walks, plays, etc.)4 Angers1 Escapes (negligible motor and sensory input)1 “Anxioius-es”2 ”Euphorics”2 Laughs1 Aggresses1 Fears, fights, flights1 Interpersonally attends (body, verbal or sensory contact)8 Envies1 Greeds1 Total:100% +/- 20% of time involvement

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