Had some help with this Had some help with this presentation!presentation!

Nikki OlsonNikki Olson John DossetorJohn DossetorBanu SisBanu Sis

Nikki OlsonNikki Olson John DossetorJohn DossetorBanu SisBanu Sis

Tori Tori SheldonSheldon

Tori Tori SheldonSheldon

ThomasThomasMuellerMuellerThomasThomasMuellerMueller

Bruce KaplanBruce KaplanBruce KaplanBruce Kaplan

Sheila Sheila Moriber KatzMoriber KatzSheila Sheila Moriber KatzMoriber Katz

Having fun creating order out of Having fun creating order out of chaos. Bird formations at edge of chaos. Bird formations at edge of Iguassu Falls!Iguassu Falls!

The Banff consensus The Banff consensus process is like that!process is like that!

Worldwide standard Worldwide standard for interpretation of for interpretation of

solid organ solid organ transplant biopsies.transplant biopsies.

The Banff consensus The Banff consensus process is like that!process is like that!

Worldwide standard Worldwide standard for interpretation of for interpretation of

solid organ solid organ transplant biopsies.transplant biopsies.

Banff Classification: Banff Classification: MilestonesMilestones 1991 First Conference1991 First Conference

1993 First Kidney International publication1993 First Kidney International publication

1995 Integration with CADI 1995 Integration with CADI

1997 Integration with CCTT classification1997 Integration with CCTT classification

1999 Second KI paper. Clinical practice guidelines. Implantation 1999 Second KI paper. Clinical practice guidelines. Implantation biopsies, microwave.biopsies, microwave.

2001 Classification of antibody-mediated rejection2001 Classification of antibody-mediated rejection

Regulatory agencies participatingRegulatory agencies participating

2003 Genomics focus, ptc cell accumulation scoring2003 Genomics focus, ptc cell accumulation scoring

2005 Gene chip analysis. Elimination of CAN, identification of chronic 2005 Gene chip analysis. Elimination of CAN, identification of chronic antibody-mediated rejection.antibody-mediated rejection.

2007 First meeting far from a town called “Banff” – La Coruna, Spain.2007 First meeting far from a town called “Banff” – La Coruna, Spain.

Diagnostic CategoriesDiagnostic Categories

1. Normal 1. Normal

2. Antibody-mediated rejection, 2. Antibody-mediated rejection,

3. Borderline changes: ‘Suspicious’ for acute cellular 3. Borderline changes: ‘Suspicious’ for acute cellular rejection rejection

4. T-cell-mediated rejection (may coincide with 4. T-cell-mediated rejection (may coincide with categories 2 and 5 and 6)categories 2 and 5 and 6)

5. Sclerosis, interstitial fibrosis, and tubular atrophy, no 5. Sclerosis, interstitial fibrosis, and tubular atrophy, no evidence of any specific etiology evidence of any specific etiology

6. Other Changes not considered to be due to rejection6. Other Changes not considered to be due to rejection

Lesion Scoring (0-3+)Lesion Scoring (0-3+)

Transplant glomerulitis - gTransplant glomerulitis - g

Chronic transplant glomerulopathy - cgChronic transplant glomerulopathy - cg

Interstitial Inflammation - IInterstitial Inflammation - I

Interstitial fibrosis - ciInterstitial fibrosis - ci

Tubulitis - tTubulitis - t

Tubular atrophy - ctTubular atrophy - ct

Vasculitis, intimal arteritis - vVasculitis, intimal arteritis - v

Fibrous intimal thickening - cvFibrous intimal thickening - cv

Arteriolar hyaline thickening - ahArteriolar hyaline thickening - ah

Mesangial matrix increase - mmMesangial matrix increase - mm

Peritubular capillary cell accumulation - ptc (still being tested)Peritubular capillary cell accumulation - ptc (still being tested)

My main interest a year ago: My main interest a year ago: Consensus Generation Online…Consensus Generation Online…

A good example of successful A good example of successful use is the World Wide Web use is the World Wide Web Consortium. “We reject kings, Consortium. “We reject kings, presidents, and voting. We presidents, and voting. We believe in rough consensus believe in rough consensus and running code.” David and running code.” David Clark (MIT) Clark (MIT)

““Consensus stops the majority Consensus stops the majority ruling the minority and is more ruling the minority and is more consistent with anarchist consistent with anarchist principles.” Anarchist FAQ. principles.” Anarchist FAQ.

ConsensUs: Computer-ConsensUs: Computer-moderated Structured moderated Structured Discourse. Discourse. http://http://faculty.washington.edu/gmobufaculty.washington.edu/gmobus/consensus.htmls/consensus.html

FacilitatePro – Online collab. FacilitatePro – Online collab. tool.tool.

A good example of successful A good example of successful use is the World Wide Web use is the World Wide Web Consortium. “We reject kings, Consortium. “We reject kings, presidents, and voting. We presidents, and voting. We believe in rough consensus believe in rough consensus and running code.” David and running code.” David Clark (MIT) Clark (MIT)

““Consensus stops the majority Consensus stops the majority ruling the minority and is more ruling the minority and is more consistent with anarchist consistent with anarchist principles.” Anarchist FAQ. principles.” Anarchist FAQ.

ConsensUs: Computer-ConsensUs: Computer-moderated Structured moderated Structured Discourse. Discourse. http://http://faculty.washington.edu/gmobufaculty.washington.edu/gmobus/consensus.htmls/consensus.html

FacilitatePro – Online collab. FacilitatePro – Online collab. tool.tool.

… … and the role of protest.and the role of protest.

(I actually believe if Banff meeting (I actually believe if Banff meeting participants knew I researched participants knew I researched this stuff as a science, my this stuff as a science, my mediator role would be much less mediator role would be much less effective. So shhh! Mums the effective. So shhh! Mums the word!)word!)

(I actually believe if Banff meeting (I actually believe if Banff meeting participants knew I researched participants knew I researched this stuff as a science, my this stuff as a science, my mediator role would be much less mediator role would be much less effective. So shhh! Mums the effective. So shhh! Mums the word!)word!)

Genomics versus traditional pathology. A Genomics versus traditional pathology. A foot firmly planted in both camps but it foot firmly planted in both camps but it seemed OK!seemed OK!

A principal investigator in Phil A principal investigator in Phil Halloran’s 18 Million Dollar Genome Halloran’s 18 Million Dollar Genome Canada transplant transcriptome Canada transplant transcriptome project.project. http://www.transcriptome.ca/http://www.transcriptome.ca/

The prime mover behind the Banff The prime mover behind the Banff Conferences and Classification which Conferences and Classification which mainly uses techniques of thirty to fifty mainly uses techniques of thirty to fifty years ago. years ago. http://http://cybernephrology.ualberta.cacybernephrology.ualberta.ca/Banff//Banff/

Affymetrix GeneChip® probe array. Affymetrix GeneChip® probe array. Image courtesy of Affymetrix.Image courtesy of Affymetrix.

Affymetrix GeneChip® probe array. Affymetrix GeneChip® probe array. Image courtesy of Affymetrix.Image courtesy of Affymetrix.

Then in late August 2006 something Then in late August 2006 something happened which changed happened which changed everything!everything!

On the same day my two best friends in science and most long On the same day my two best friends in science and most long standing collaborators made diametrically opposite and standing collaborators made diametrically opposite and counterbalancing suggestions:counterbalancing suggestions:

1) That we own up to all our errors of the past in traditional 1) That we own up to all our errors of the past in traditional pathology and tie our future to the undeniable truth of genomics, pathology and tie our future to the undeniable truth of genomics, rejecting from consideration the wealth of validating findings rejecting from consideration the wealth of validating findings coming from the use of traditional pathology in the last 15 years.coming from the use of traditional pathology in the last 15 years.

2) That because it is rather difficult to decide what the relationship 2) That because it is rather difficult to decide what the relationship of genomics findings to traditional pathology is, we should leave of genomics findings to traditional pathology is, we should leave genomics out of future transplant pathology meetings.genomics out of future transplant pathology meetings.

Above are just two examples of a general tendency to exclude one Above are just two examples of a general tendency to exclude one or the other modality from consideration, difficult to think of both or the other modality from consideration, difficult to think of both at once. Many common entities have no known genomics signature at once. Many common entities have no known genomics signature as yet.as yet.

There is a new search underway for genomics functional correlates, There is a new search underway for genomics functional correlates, reminiscent of morphologic functional correlates of the ‘70s. Many reminiscent of morphologic functional correlates of the ‘70s. Many patients with injury gene expression on biopsy have normal patients with injury gene expression on biopsy have normal function.function.

There seemed looming here some enormous gulfs that only There seemed looming here some enormous gulfs that only philosophy (and creativity!) could span and make sense of. I began philosophy (and creativity!) could span and make sense of. I began steeping myself in philosophy in earnest seeking the help of others steeping myself in philosophy in earnest seeking the help of others who could advise me!who could advise me!

Methods and ResultsMethods and Results

Methods: We compared histological analysis of renal allograft Methods: We compared histological analysis of renal allograft biopsy assessed by the Banff criteria to biological evidence of T biopsy assessed by the Banff criteria to biological evidence of T cell mediated rejection assessed by Affymetrix microarrays and cell mediated rejection assessed by Affymetrix microarrays and clinical evidence of rejection based on retrospective chart review clinical evidence of rejection based on retrospective chart review in 30 biopsies for cause with tubulitis. We applied various in 30 biopsies for cause with tubulitis. We applied various philosophers’ approaches to truth and meaning to “clinical philosophers’ approaches to truth and meaning to “clinical truth”, the diagnosis at the time of biopsy as assessed by chart truth”, the diagnosis at the time of biopsy as assessed by chart review, and to what “seeing” means when we say we “see” review, and to what “seeing” means when we say we “see” biopsy evidence of specific disease processes, drawing from the biopsy evidence of specific disease processes, drawing from the writings of Dewey, Kierkegaard, Fromm, Foucault, Polanyi, writings of Dewey, Kierkegaard, Fromm, Foucault, Polanyi, Stempsey, and Beard. Stempsey, and Beard.

Results: Questions of diagnosis when biopsy histopathology, gene Results: Questions of diagnosis when biopsy histopathology, gene chip analysis, and clinical data appear in conflict give rise to chip analysis, and clinical data appear in conflict give rise to circular arguments, which are clarified and made easier to accept circular arguments, which are clarified and made easier to accept when philosophical concepts such as Socratic dialogue, tacit when philosophical concepts such as Socratic dialogue, tacit knowing, the epistemic gap, and ‘thing knowledge’ are applied. knowing, the epistemic gap, and ‘thing knowledge’ are applied. Cases where there is agreement on basic diagnosis but Cases where there is agreement on basic diagnosis but disagreement on severity or duration of the process also can be disagreement on severity or duration of the process also can be better understood applying these philosophical approaches to the better understood applying these philosophical approaches to the data available from the three modalities; 30% of biopsy cases (9 data available from the three modalities; 30% of biopsy cases (9 of 30) had data in conflict and benefited from applying of 30) had data in conflict and benefited from applying philosophy. philosophy.

Example of Data in Conflict, Not So Much Example of Data in Conflict, Not So Much a Conflict As A Different Way of Looking!a Conflict As A Different Way of Looking!

Biopsy #1 on patient:Biopsy #1 on patient:

Traditional Pathology: Acute Cellular Rejection Traditional Pathology: Acute Cellular Rejection (Tubulointerstitial) Rule out anti-tubular basement (Tubulointerstitial) Rule out anti-tubular basement membrane antibody nephritis, glomerular features membrane antibody nephritis, glomerular features consistent with chronic transplant glomerulopathy, consistent with chronic transplant glomerulopathy, moderate hyaline arteriolar thickening suggesting moderate hyaline arteriolar thickening suggesting calcineurin inhibitor toxicitycalcineurin inhibitor toxicity

Gene Chip: Acute Cellular RejectionGene Chip: Acute Cellular Rejection

Biopsy #2 on same patient three weeks later: Biopsy #2 on same patient three weeks later:

Traditional Pathology: Probable calcineurin inhibitor Traditional Pathology: Probable calcineurin inhibitor toxicity, previous tubulointerstitial rejection toxicity, previous tubulointerstitial rejection appears to have resolved although antitubular appears to have resolved although antitubular basement membrane antibody is still evident by basement membrane antibody is still evident by immunofluorescence.immunofluorescence.

Gene Chip: Acute Cellular RejectionGene Chip: Acute Cellular Rejection

Philosophy – PlatoPhilosophy – PlatoHow to examine life?How to examine life?

Philosophy – Pathology We are actually Philosophy – Pathology We are actually fulfilling the expectations of the fulfilling the expectations of the Philosopher’s Stone!Philosopher’s Stone!

The Philosopher's Stone. This mythical, magical article was The Philosopher's Stone. This mythical, magical article was said to possess the ability to change base metals into gold said to possess the ability to change base metals into gold and could also, if mixed judiciously with wine, produce the and could also, if mixed judiciously with wine, produce the Elixir of Life - a comprehensive cure-all for most illnesses. Elixir of Life - a comprehensive cure-all for most illnesses.

We turn glass, wax, and organic matter into gold We turn glass, wax, and organic matter into gold (administration sees this most clearly!) and in the (administration sees this most clearly!) and in the process diagnose and cure illnesses. We are the process diagnose and cure illnesses. We are the modern alchemists! Even doing it without wine! modern alchemists! Even doing it without wine!

Lara Croft and the Philosopher’s Stone Lara Croft and the Philosopher’s Stone in the videogame Tomb Raider 5in the videogame Tomb Raider 5

Lara Croft and the Philosopher’s Stone Lara Croft and the Philosopher’s Stone in the videogame Tomb Raider 5in the videogame Tomb Raider 5

Harry PotterHarry PotterPhilosopher’s StonePhilosopher’s Stone

Harry PotterHarry PotterPhilosopher’s StonePhilosopher’s Stone

Philosophy – Pathology 1559 Philosophy – Pathology 1559 Alchemist Engraving from Alchemist Engraving from Peter Peter Bruegel the Elder Bruegel the Elder Interesting to Interesting to

compare our compare our labs today to labs today to the the alchemist’s alchemist’s lab of 1559!lab of 1559!

Bruegel Bruegel considered his considered his fellow humans fellow humans to be at the to be at the mercy of folly; mercy of folly; to be to be eccentric as a eccentric as a species, apart species, apart from nature from nature yet exhibiting yet exhibiting a distincta distinct humanhuman nature.nature.

Bruegel Bruegel depicted depicted many crowd many crowd scenes scenes showing with showing with wit a range of wit a range of human human behaviors in behaviors in encyclopedic encyclopedic detail. detail.

Philosophy – Pathology 1559 Two sides Philosophy – Pathology 1559 Two sides theme: Breugel’s The Fight Between theme: Breugel’s The Fight Between Carnival and Lent.Carnival and Lent. Breugel’s Breugel’s

The Fight The Fight Between Between Carnival and Carnival and Lent depicts Lent depicts the contrast the contrast between two between two sides of sides of contemporarcontemporary life, as can y life, as can be seen by be seen by the the appearance appearance of the inn on of the inn on the left side - the left side - for for enjoyment, enjoyment, and the and the church on church on the right the right side - for side - for religious religious observance. observance.

You can You can imagine imagine genomics on genomics on one side and one side and traditional traditional path on path on other!other!

Philosophy – Question Philosophy – Question everything. Trust no one? everything. Trust no one? “The Wisdom of Crowds”“The Wisdom of Crowds”

Studying philosophy immediately calls into question the Studying philosophy immediately calls into question the wisdom of experts, and so is very humbling to me, as wisdom of experts, and so is very humbling to me, as someone with the largest practice of expert consultation in someone with the largest practice of expert consultation in renal transplant pathology. James Surowiecki’s “The renal transplant pathology. James Surowiecki’s “The Wisdom of Crowds” suggests that groups rather than Wisdom of Crowds” suggests that groups rather than individuals will often be better at arriving at the correct individuals will often be better at arriving at the correct answer. It is obviously desirable to be “right” when making answer. It is obviously desirable to be “right” when making diagnoses that are acted on clinically, but in the central slide diagnoses that are acted on clinically, but in the central slide review I do for many international clinical trials it is more review I do for many international clinical trials it is more desirable to be “consistent” than “right”. So maybe an desirable to be “consistent” than “right”. So maybe an individual is still better there. It is a philosophical point!individual is still better there. It is a philosophical point!

Studying philosophy immediately calls into question the Studying philosophy immediately calls into question the wisdom of experts, and so is very humbling to me, as wisdom of experts, and so is very humbling to me, as someone with the largest practice of expert consultation in someone with the largest practice of expert consultation in renal transplant pathology. James Surowiecki’s “The renal transplant pathology. James Surowiecki’s “The Wisdom of Crowds” suggests that groups rather than Wisdom of Crowds” suggests that groups rather than individuals will often be better at arriving at the correct individuals will often be better at arriving at the correct answer. It is obviously desirable to be “right” when making answer. It is obviously desirable to be “right” when making diagnoses that are acted on clinically, but in the central slide diagnoses that are acted on clinically, but in the central slide review I do for many international clinical trials it is more review I do for many international clinical trials it is more desirable to be “consistent” than “right”. So maybe an desirable to be “consistent” than “right”. So maybe an individual is still better there. It is a philosophical point!individual is still better there. It is a philosophical point!

Philosophy – But Descartes 1596-1650, Philosophy – But Descartes 1596-1650, Father of Modern Philosophy (“I think, Father of Modern Philosophy (“I think, therefore I am”) did not trust crowds, therefore I am”) did not trust crowds, trusted only himself!trusted only himself!Argued for individual autonomy.Argued for individual autonomy.

““A majority vote is worthless as a A majority vote is worthless as a proof of truths that are at all proof of truths that are at all difficult to discover, for a single difficult to discover, for a single man is much more likely to hit man is much more likely to hit upon them than a group of people. upon them than a group of people. I was, then, unable to choose I was, then, unable to choose anyone whose opinions struck me anyone whose opinions struck me as  preferable to those of others, as  preferable to those of others, and I found myself as it were and I found myself as it were forced to become my own guide"forced to become my own guide"

p.28 "Discourse on the Method"p.28 "Discourse on the Method"from from Descartes: Selected Descartes: Selected Philosophical WritingsPhilosophical Writings

Argued for individual autonomy.Argued for individual autonomy.““A majority vote is worthless as a A majority vote is worthless as a proof of truths that are at all proof of truths that are at all difficult to discover, for a single difficult to discover, for a single man is much more likely to hit man is much more likely to hit upon them than a group of people. upon them than a group of people. I was, then, unable to choose I was, then, unable to choose anyone whose opinions struck me anyone whose opinions struck me as  preferable to those of others, as  preferable to those of others, and I found myself as it were and I found myself as it were forced to become my own guide"forced to become my own guide"

p.28 "Discourse on the Method"p.28 "Discourse on the Method"from from Descartes: Selected Descartes: Selected Philosophical WritingsPhilosophical Writings

More Descartes - He Had Nice Things to More Descartes - He Had Nice Things to Say About the Future of Medicine in Say About the Future of Medicine in 1637!1637!... health, which is undoubtedly the chief good and the foundation of all the other goods in this life. For even the mind depends so much on the temperament and disposition of the bodily organs that if it is possible to find some means of making men in general wiser and more skilful than they have been up till now, I believe we must look for it in medicine. It is true that medicine as currently practiced does not contain much of any significant use; but without intending to disparage it, I am sure there is no one, even among its practitioners, who would not admit that all we know in medicine is almost nothing in comparison with what remains to be known, and that we might free ourselves from innumerable diseases, both of the body and of the mind, and perhaps even from the infirmity of old age, if we had sufficient knowledge of their causes and of all the remedies that nature has provided. Descartes, Discourse on the Method, 1637, Selected philosophical writings. Cambridge (Cambridge University Press), 1988, p.47.

... health, which is undoubtedly the chief good and the foundation of all the other goods in this life. For even the mind depends so much on the temperament and disposition of the bodily organs that if it is possible to find some means of making men in general wiser and more skilful than they have been up till now, I believe we must look for it in medicine. It is true that medicine as currently practiced does not contain much of any significant use; but without intending to disparage it, I am sure there is no one, even among its practitioners, who would not admit that all we know in medicine is almost nothing in comparison with what remains to be known, and that we might free ourselves from innumerable diseases, both of the body and of the mind, and perhaps even from the infirmity of old age, if we had sufficient knowledge of their causes and of all the remedies that nature has provided. Descartes, Discourse on the Method, 1637, Selected philosophical writings. Cambridge (Cambridge University Press), 1988, p.47.

Philosophy – Science and PhilosophyPhilosophy – Science and Philosophy

In some cases we have theories In some cases we have theories which cannot yet be tested. In which cannot yet be tested. In these cases, choosing between these cases, choosing between competing theories is more a competing theories is more a matter of philosophy than of matter of philosophy than of science.science.

Later, when technology allows for Later, when technology allows for tests to be made, the theories tests to be made, the theories then can become scientific.then can become scientific.

The concept of cells existed in The concept of cells existed in philosophy long before the philosophy long before the invention of the microscope and invention of the microscope and confirmation of their existence in confirmation of their existence in science.science.

In some cases we have theories In some cases we have theories which cannot yet be tested. In which cannot yet be tested. In these cases, choosing between these cases, choosing between competing theories is more a competing theories is more a matter of philosophy than of matter of philosophy than of science.science.

Later, when technology allows for Later, when technology allows for tests to be made, the theories tests to be made, the theories then can become scientific.then can become scientific.

The concept of cells existed in The concept of cells existed in philosophy long before the philosophy long before the invention of the microscope and invention of the microscope and confirmation of their existence in confirmation of their existence in science.science.

Philosophy Of SciencePhilosophy Of Science

Watch this space!

Philosophy – Conflict between Philosophy – Conflict between philosophy and science.philosophy and science.

Both have their place.Both have their place.

““I can always figure a case out if I justI can always figure a case out if I justspend enough time with it!”spend enough time with it!”

I thought I had a way to tell reflectiveI thought I had a way to tell reflectivepathologists – they use mechanical stage - pathologists – they use mechanical stage - commonly used for renal pathology, but commonly used for renal pathology, but just an irritant for general surgical just an irritant for general surgical pathologist pathologist (“sprong” vs. “thwak” sound) who want to (“sprong” vs. “thwak” sound) who want to pass the pass the glass across the stage as quickly as glass across the stage as quickly as possible. possible. But then I discovered that Bob Colvin, Chair But then I discovered that Bob Colvin, Chair at MGH, does not use mechanical stage! at MGH, does not use mechanical stage!

Philosophy – Armchair-reflective Philosophy – Armchair-reflective pathology vs. Blink-instinctive, shoot-pathology vs. Blink-instinctive, shoot-from-the-hip.from-the-hip.

Philosophy – Armchair-reflective Philosophy – Armchair-reflective pathology vs. Blink-instinctive, shoot-pathology vs. Blink-instinctive, shoot-from-the-hip.from-the-hip.

Philosophy – Socrates and thePhilosophy – Socrates and theOracle of DelphiOracle of Delphi

When Socrates friend Chaerephon asked the Oracle of Delphi who was the wisest, the Oracle responded with the words “none is wiser than Socrates”. As a result, Socrates began his mission to find  men who were in fact wiser than he; to prove the Oracle wrong.  He first went to a politician, a man reputed to be wise. Through questioning the man, he find he was not wise because he claimed to know what he did not. Socrates pointed this out; this made the politican indignant.  The same happened with a poet and artisan. Because they were skillful in their own art, they assumed themselves to be skillful in matters of great importance such as truth and virtue. This obscured their real wisdom. Socrates concluded that he was wise only in so far as he know that he knew nothing. It was his mission in life to publicly question the assumptions of others, regardless of the negative consequences. This use of Socratic questioning forces people to examine their own beliefs and the validity of such beliefs. This method can be valuably applied to assessing new technology.

When Socrates friend Chaerephon asked the Oracle of Delphi who was the wisest, the Oracle responded with the words “none is wiser than Socrates”. As a result, Socrates began his mission to find  men who were in fact wiser than he; to prove the Oracle wrong.  He first went to a politician, a man reputed to be wise. Through questioning the man, he find he was not wise because he claimed to know what he did not. Socrates pointed this out; this made the politican indignant.  The same happened with a poet and artisan. Because they were skillful in their own art, they assumed themselves to be skillful in matters of great importance such as truth and virtue. This obscured their real wisdom. Socrates concluded that he was wise only in so far as he know that he knew nothing. It was his mission in life to publicly question the assumptions of others, regardless of the negative consequences. This use of Socratic questioning forces people to examine their own beliefs and the validity of such beliefs. This method can be valuably applied to assessing new technology.

Two pathologist’s lesion scores vs probability of clinical rejection episode (classifier was built based on gene expression in biopsies for

cause)

Being a reflective pathologist is not working all the time….Besides pathology suffers from interobserver variability!!

D3 classifier probability

Classifier was built based on expression of three independent gene sets in 143 renal allograft biopsies for cause in order to predict

clinical rejection episodes

R2 = 0.82

R2 = 0.81

R2 = 0.78

-0.5

0

0.5

1

1.5

2

0 0.2 0.4 0.6 0.8 1

hmCATr

hmtGRITcr

hmRT

Linear(hmtGRITcr)

Gene expression analysis should emerge as a complementary dimension to pathology, not a

competitor.

The emergence of microarrays for genome-wide transcriptome The emergence of microarrays for genome-wide transcriptome analysis offers potential for objective and quantitative analysis offers potential for objective and quantitative diagnosis as well as insights into pathogenesis. diagnosis as well as insights into pathogenesis.

A major advantage of gene expression measurements in A major advantage of gene expression measurements in diagnosis is reduction of the sources of variability compared to diagnosis is reduction of the sources of variability compared to histology. histology.

Microarray analysis should be complementary to histology, not Microarray analysis should be complementary to histology, not a competitor.a competitor.

Both gene expression and pathology are empirical data to Both gene expression and pathology are empirical data to distinguish diseased from normal tissue, but do not forget: both distinguish diseased from normal tissue, but do not forget: both are footprints of the truth, except that pathology includes much are footprints of the truth, except that pathology includes much more nonspecificity than gene expression, whereas we do not more nonspecificity than gene expression, whereas we do not know the genomics signature of many conditions yet.know the genomics signature of many conditions yet.

The transcriptome: The transcriptome: our new microscopeour new microscope

Microarray analysis of gene expression extends a bridge between pathology

and the truth, helps us to determine disease phenotypes more accurately,

uncovers mechanism(s) of rejection and other diseases, and finally teaches us how to use microscope – more than 400 years after its

invention!

Philosophy – Socratic methodPhilosophy – Socratic method

Philosophy – TruthPhilosophy – TruthPhilosophy of Science – Karl PopperPhilosophy of Science – Karl Popper

Popper concluded that all we know is but "a woven web of Popper concluded that all we know is but "a woven web of guesses," guesses," that while empirical generalizations may not be verifiable, they that while empirical generalizations may not be verifiable, they are, at least, falsifable. are, at least, falsifable.

Popper concluded that all we know is but "a woven web of Popper concluded that all we know is but "a woven web of guesses," guesses," that while empirical generalizations may not be verifiable, they that while empirical generalizations may not be verifiable, they are, at least, falsifable. are, at least, falsifable.

Sir Karl PopperSir Karl Popper(1902-1994)(1902-1994)

Professor of Logic and Professor of Logic and Scientific Method Scientific Method

at the London School at the London School of Economics for 23 of Economics for 23

yearsyears

Sir Karl PopperSir Karl Popper(1902-1994)(1902-1994)

Professor of Logic and Professor of Logic and Scientific Method Scientific Method

at the London School at the London School of Economics for 23 of Economics for 23

yearsyears

Uncertainty about Truth comes from Uncertainty about Truth comes from both Classical Philosophy and both Classical Philosophy and Quantum PhysicsQuantum Physics Problem of Induction - David Hume (1711-1776) Problem of Induction - David Hume (1711-1776)

Contended that until we know the Necessary Contended that until we know the Necessary Connection /cause of things then all human Connection /cause of things then all human knowledge is uncertain, merely a habit of thinking knowledge is uncertain, merely a habit of thinking based upon repeated observation (induction), and based upon repeated observation (induction), and which depends upon the future being like the past. which depends upon the future being like the past.

Heisenberg Uncertainty Principle - Werner Heisenberg Uncertainty Principle - Werner Heisenberg (1901-1976) Applies to the position Heisenberg (1901-1976) Applies to the position and momentum of a single particle, and implies and momentum of a single particle, and implies that if we continue increasing the accuracy with that if we continue increasing the accuracy with which one of these is measured, there will come a which one of these is measured, there will come a point at which the other must be measured with point at which the other must be measured with less accuracy. Can be extrapolated to general less accuracy. Can be extrapolated to general uncertainty about physical state of the world.uncertainty about physical state of the world.

Philosophy – William James – Philosophy – William James – Truth is PragmaticTruth is Pragmatic Truth is a property of certain ideas. These ideas, in order to be true, are those which we can verify. To verify is to lead us through the ideas that allow our experience to remain in agreement with what is being verified. Therefore, truth is whatever idea starts the verification process. Truth is grounded in purpose. The intent of the verification process is to see if the idea is functional in experience, thus useful. Useful is defined as being of practical use. If one experience leads us to other moments that are worthwhile, then they have truth because they have been purposeful. The truths in these experiences are not important at all times, thus we have ‘extra truths’. When the extra truth becomes practically relevant towards leading us to other worthwhile moments, it is used. For example, we assume Japan to exist without ever having been there because it works to do so. Because there is nothing interfering with that belief, we can safely assume it exists. Therefore, truth runs on a ‘credit system’, meaning that as long as your thoughts and beliefs are not challenged, they are valid.

Truth is a property of certain ideas. These ideas, in order to be true, are those which we can verify. To verify is to lead us through the ideas that allow our experience to remain in agreement with what is being verified. Therefore, truth is whatever idea starts the verification process. Truth is grounded in purpose. The intent of the verification process is to see if the idea is functional in experience, thus useful. Useful is defined as being of practical use. If one experience leads us to other moments that are worthwhile, then they have truth because they have been purposeful. The truths in these experiences are not important at all times, thus we have ‘extra truths’. When the extra truth becomes practically relevant towards leading us to other worthwhile moments, it is used. For example, we assume Japan to exist without ever having been there because it works to do so. Because there is nothing interfering with that belief, we can safely assume it exists. Therefore, truth runs on a ‘credit system’, meaning that as long as your thoughts and beliefs are not challenged, they are valid.

Philosophy – Tacit Knowledge – Philosophy – Tacit Knowledge – Michael Polanyi – Knowledge is Michael Polanyi – Knowledge is personal.personal.

Recognizing Tacit Knowledge Recognizing Tacit Knowledge In Medical EpistemologyIn Medical Epistemology

Theor Med Bioeth. 2006;27(3):187-213. Theor Med Bioeth. 2006;27(3):187-213.

Recognizing tacit knowledge in medical epistemology.Recognizing tacit knowledge in medical epistemology.

Henry SGHenry SG..

Center for Biomedical Ethics and Society, Vanderbilt University Medical Center for Biomedical Ethics and Society, Vanderbilt University Medical Center, 319 Oxford House, Nashville, TN 37232-4350, USA. Center, 319 Oxford House, Nashville, TN 37232-4350, USA. shenry@alumni.vanderbilt.edushenry@alumni.vanderbilt.edu

The evidence-based medicine movement advocates basing all medical The evidence-based medicine movement advocates basing all medical decisions on certain types of quantitative research data and has decisions on certain types of quantitative research data and has stimulated protracted controversy and debate since its inception. stimulated protracted controversy and debate since its inception. Evidence-based medicine presupposes an inaccurate and deficient view Evidence-based medicine presupposes an inaccurate and deficient view of medical knowledge. Michael Polanyi's theory of tacit knowledge both of medical knowledge. Michael Polanyi's theory of tacit knowledge both explains this deficiency and suggests remedies for it. Polanyi shows how explains this deficiency and suggests remedies for it. Polanyi shows how all explicit human knowledge depends on a wealth of tacit knowledge all explicit human knowledge depends on a wealth of tacit knowledge which accrues from experience and is essential for problem solving. which accrues from experience and is essential for problem solving. Edmund Pellegrino's classic treatment of clinical judgment is examined, Edmund Pellegrino's classic treatment of clinical judgment is examined, and a Polanyian critique of this position demonstrates that tacit and a Polanyian critique of this position demonstrates that tacit knowledge is necessary for understanding how clinical judgment and knowledge is necessary for understanding how clinical judgment and medical decisions involve persons. An adequate medical epistemology medical decisions involve persons. An adequate medical epistemology requires much more qualitative research relevant to the clinical requires much more qualitative research relevant to the clinical encounter and medical decision making than is currently being done. This encounter and medical decision making than is currently being done. This research is necessary for preventing an uncritical application of research is necessary for preventing an uncritical application of evidence-based medicine by health care managers that erodes good evidence-based medicine by health care managers that erodes good clinical practice. Polanyi's epistemology shows the need for this work and clinical practice. Polanyi's epistemology shows the need for this work and provides the structural core for building an adequate and robust medical provides the structural core for building an adequate and robust medical epistemology that moves beyond evidence-based medicine.epistemology that moves beyond evidence-based medicine.

Philosophy – Zombies – Epistemic Philosophy – Zombies – Epistemic GapGap

Perception versus reality. A zombie is a hypothetical creature Perception versus reality. A zombie is a hypothetical creature that is physically identical to a conscious being but is not that is physically identical to a conscious being but is not conscious at all. Many people hold that zombies are conscious at all. Many people hold that zombies are conceivable in principle, and hold further that in principle one conceivable in principle, and hold further that in principle one could conceive of a zombie world: one that is physically could conceive of a zombie world: one that is physically identical to ours, but without consciousness. identical to ours, but without consciousness.

Perception versus reality. A zombie is a hypothetical creature Perception versus reality. A zombie is a hypothetical creature that is physically identical to a conscious being but is not that is physically identical to a conscious being but is not conscious at all. Many people hold that zombies are conscious at all. Many people hold that zombies are conceivable in principle, and hold further that in principle one conceivable in principle, and hold further that in principle one could conceive of a zombie world: one that is physically could conceive of a zombie world: one that is physically identical to ours, but without consciousness. identical to ours, but without consciousness.

Philosophy – Bertrand RussellPhilosophy – Bertrand Russell

““Philosophy is practical because it frees the Philosophy is practical because it frees the mind from narrow interests and is exercise mind from narrow interests and is exercise for the mind. It aims at understanding, for the mind. It aims at understanding, opening up possibilities of living in a more opening up possibilities of living in a more complex world. Philosophy does this by complex world. Philosophy does this by unifying and systematizing knowledge, unifying and systematizing knowledge, opening up unexpected possibilities in terms opening up unexpected possibilities in terms of thinking.”of thinking.”

Philosophy – The MatrixPhilosophy – The Matrix

By choosing the red pill, Neo becomes a trailblazer. What is fundamental to the human condition is to question our environment. If we do not do so, we are treating ourselves as mere inanimate objects. We are hard-wired to enquire.

By choosing the red pill, Neo becomes a trailblazer. What is fundamental to the human condition is to question our environment. If we do not do so, we are treating ourselves as mere inanimate objects. We are hard-wired to enquire.

Philosophy – Italo CalvinoPhilosophy – Italo Calvino

Argued for the dismantling of Argued for the dismantling of interdisciplinary barriers, getting interdisciplinary barriers, getting rid of departments of philosophy: rid of departments of philosophy: "We will not have a culture equal "We will not have a culture equal to the challenge until we compare to the challenge until we compare against one another the basic against one another the basic problematics of science, problematics of science, philosophy, and literature, in order philosophy, and literature, in order to call them all into question." to call them all into question."

One might imagine a day when One might imagine a day when people would argue for getting rid people would argue for getting rid of departments of pathology!of departments of pathology!

Philosophy – Michel Foucault – What Philosophy – Michel Foucault – What do we mean by “seeing” in do we mean by “seeing” in medicine?medicine?

The gaze of the physicians in modernity could penetrate illusions of sickness and other symptoms to see through to the underlying reality of disease, the hidden truth. In the process physicians have developed their own myths.

The gaze of the physicians in modernity could penetrate illusions of sickness and other symptoms to see through to the underlying reality of disease, the hidden truth. In the process physicians have developed their own myths.

Philosophy – Man machine Philosophy – Man machine collaborationcollaboration

Philosophy – Thing KnowledgePhilosophy – Thing Knowledge

Western philosophers have traditionally Western philosophers have traditionally concentrated on theory as the means for concentrated on theory as the means for expressing knowledge about a variety of expressing knowledge about a variety of phenomena. This absorbing book challenges phenomena. This absorbing book challenges this fundamental notion by showing how this fundamental notion by showing how objects themselves, specifically scientific objects themselves, specifically scientific instruments, can express knowledge. As he instruments, can express knowledge. As he considers numerous intriguing examples, Davis considers numerous intriguing examples, Davis Baird gives us the tools to "read" the material Baird gives us the tools to "read" the material products of science and technology and to products of science and technology and to understand their place in culture. Making a understand their place in culture. Making a provocative and original challenge to our provocative and original challenge to our conception of knowledge itself, conception of knowledge itself, Thing Thing Knowledge Knowledge demands that we take a new look at demands that we take a new look at theories of science and technology, knowledge, theories of science and technology, knowledge, progress, and change. Baird considers a wide progress, and change. Baird considers a wide range of instruments, including Faraday's first range of instruments, including Faraday's first electric motor, eighteenth-century mechanical electric motor, eighteenth-century mechanical models of the solar system, the cyclotron, models of the solar system, the cyclotron, various instruments developed by analytical various instruments developed by analytical chemists between 1930 and 1960, chemists between 1930 and 1960, spectrometers, and more.spectrometers, and more.

Philosophy – Role in Development of Philosophy – Role in Development of Existing Clinical Trial MethodologyExisting Clinical Trial Methodology

Ways to Decrease Bias in Search for Truth:Ways to Decrease Bias in Search for Truth:

Double-blind TestingDouble-blind Testing

There are 16,700 There are 16,700 web imagesweb images

entitled entitled ““The Search For Truth”!The Search For Truth”!

There are 16,700 There are 16,700 web imagesweb images

entitled entitled ““The Search For Truth”!The Search For Truth”!

Philosophy – Innovation - CreativityPhilosophy – Innovation - Creativity

Creativity can be taught! “Interactive Creativity can be taught! “Interactive Screen” course in Banff summer of 2005.Screen” course in Banff summer of 2005.

Frank Boyd – Creative LondonFrank Boyd – Creative London

Creative Director of BBCCreative Director of BBC

BBC Creativity ProjectBBC Creativity Project

““the most creative organisation in the the most creative organisation in the world”?world”?

BrainstormingBrainstorming

Appoint a facilitator and capture all ideasAppoint a facilitator and capture all ideas

Go for quantity: the more ideas, the betterGo for quantity: the more ideas, the better

Work together: combine, build, extendWork together: combine, build, extend

Be playful: wild ideas are welcome.Be playful: wild ideas are welcome.

Defer judgementDefer judgement

And remember...And remember...

it’s easier to make the interesting feasible it’s easier to make the interesting feasible than to make the feasible interestingthan to make the feasible interesting

Some Literature on Creativity!Some Literature on Creativity!

Creativity Games for Trainers: A Creativity Games for Trainers: A Handbook of Group Activities for Handbook of Group Activities for Jumpstarting Workplace Creativity Jumpstarting Workplace Creativity (McGraw-Hill Training Series) (Paperback)(McGraw-Hill Training Series) (Paperback)by Robert Epstein by Robert Epstein

Thinkertoys (A Handbook of Business Thinkertoys (A Handbook of Business Creativity) (Paperback)Creativity) (Paperback)by Michael Michalko by Michael Michalko

Six Thinking Hats (Paperback)Six Thinking Hats (Paperback)by Edward De Bonoby Edward De Bono

BBC CreativityBBC Creativity

““connecting with connecting with

audiences”audiences”

We need to connect with We need to connect with audiences too! If we do audiences too! If we do it right we will be it right we will be changing the face of changing the face of medicine!medicine!

Someday the Someday the percutaneous biopsy will percutaneous biopsy will be replaced by some be replaced by some superior noninvasive superior noninvasive approach lacking the approach lacking the sampling error, sampling error, invasiveness, relative invasiveness, relative non-specificity of current non-specificity of current diagnostic assessment.diagnostic assessment.

““Wow, then we will be Wow, then we will be out of a job!”out of a job!”

vs.vs.

“Hey that will be really “Hey that will be really exciting to practice exciting to practice pathology like that!”pathology like that!”

The replacement of the The replacement of the invasive percutaneous invasive percutaneous biopsy approach by a biopsy approach by a noninvasive molecular noninvasive molecular biology/genomics biology/genomics approach has analogy in approach has analogy in major political change.major political change.

In the 80s one knew that In the 80s one knew that sometime apartheid in sometime apartheid in South Africa would end South Africa would end and the Berlin Wall would and the Berlin Wall would come down but would come down but would that happen in a day, a that happen in a day, a year, a decade, a year, a decade, a century?century?

We now await a similar We now await a similar positive tumultuous positive tumultuous change in the field of change in the field of transplantation.transplantation.

And life will be better And life will be better after than before.after than before.

We need the right We need the right approach.approach.

"Possess the right "Possess the right thinking, in this you must thinking, in this you must never lapse."never lapse."

Splinter - the ninja Splinter - the ninja master/talking rat - Teenage master/talking rat - Teenage Mutant Ninja TurtleMutant Ninja Turtle movie (1990) movie (1990)

Banff Conferences on Banff Conferences on Allograft Pathology Allograft Pathology 1991-?1991-?

Global consensus Global consensus generation while generation while maintaining intellectual maintaining intellectual freedom.freedom.

Like the mosh pit at a Like the mosh pit at a great rock concert. No great rock concert. No partner, the ultimate in partner, the ultimate in individuality, individuality, dangerous, but dangerous, but when the music when the music is good everyone is good everyone dances in sync dances in sync and life is good! and life is good!

Current ResearchCurrent Research

Microarray analysis of both human & Microarray analysis of both human & mouse kidney transplants with rejection mouse kidney transplants with rejection and other complicationsand other complications

Correlate with Clinical data & Banff Correlate with Clinical data & Banff lesions. Common entities like lesions. Common entities like glomerulonephritis, bacterial infection, glomerulonephritis, bacterial infection, and calcineurin inhibitor toxicity have no and calcineurin inhibitor toxicity have no genomics signature at present.genomics signature at present.

Human and Mouse similar genes and similar development

The Cell 2002.

Bruce Kaplan – Genomics adjunctive to Bruce Kaplan – Genomics adjunctive to another gold standard, changing a priori another gold standard, changing a priori assumptions for positive and negative assumptions for positive and negative predictive value?predictive value?

Future Banff Meetings:Future Banff Meetings:

2007 - La Coruna, Spain (June 23-29)2007 - La Coruna, Spain (June 23-29)

2009 - Whistler, British Columbia, Canada2009 - Whistler, British Columbia, Canada

2011 - Paris, France2011 - Paris, France

2013 - Banff, Alberta, Canada2013 - Banff, Alberta, Canada

2015 - Stockholm, Sweden2015 - Stockholm, Sweden

2017 - Please make a proposal!2017 - Please make a proposal!

Conclusions: Genomics vs. Conclusions: Genomics vs. Traditional Pathology.Traditional Pathology.

At the moment genomics and traditional At the moment genomics and traditional pathology are difficult to compare because pathology are difficult to compare because they do not measure the same things and they do not measure the same things and have a very different knowledge structure. have a very different knowledge structure. Philosophy, creativity, and good humor are Philosophy, creativity, and good humor are needed to consider them both in the mind at needed to consider them both in the mind at once.once.

As easy as it would be to just deal with one As easy as it would be to just deal with one and exclude the other, we really need them and exclude the other, we really need them both, as working in combination they are the both, as working in combination they are the future of diagnostic medicine!future of diagnostic medicine!

Conclusions: Fluff vs. Conclusions: Fluff vs. SubstanceSubstance

In a short time the tremendous resources and In a short time the tremendous resources and intellectual effort being devoted to transplant intellectual effort being devoted to transplant genomics and diagnostics locally in the genomics and diagnostics locally in the Genome Canada project will bring great Genome Canada project will bring great advances. Perhaps the most important will be advances. Perhaps the most important will be changes in the way we interpret and score changes in the way we interpret and score light microscopic changes (e.g. requiring i2 for light microscopic changes (e.g. requiring i2 for v1 to equal rejection etc.), so it will enhance v1 to equal rejection etc.), so it will enhance not replace traditional pathology. not replace traditional pathology.

Despite this wonderful intellectual ferment, Despite this wonderful intellectual ferment, questions will remain. The philosophical questions will remain. The philosophical approaches touched on in this presentation approaches touched on in this presentation could provide a basis for dealing with many of could provide a basis for dealing with many of them.them.

Genome Canada/Genome AlbertaUniversity Hospital FoundationAlberta Innovation and Science

Roche Molecular Systems Roche Canada Roche Organ Transplant Research Foundation (ROTRF)

Canadian Institutes of Health ResearchKidney Foundation of Canada

Alberta Heritage Foundation for Medical ResearchAstellas Canada

Muttart Chair in Clinical Immunology, Canada Research Chair in Life Sciences

Arts and Humanities in Health and Medicine Program http://www.med.ualberta.ca/education/ahhm.cfm

http://transplants.med.ualberta.cahttp:/www.transcriptome.ca/

http://cybernephrology.ualberta.ca/banffThis presentation: http://

www.cybernephrology.ualberta.ca/misc/Solez/LMP/

AcknowledgementsAcknowledgementsAcknowledgementsAcknowledgements