1. Science as Koan: Stem cells, complexity, and the science of Being All lands are in my body And so are the Buddhas living there; Watch my pores, And I will show you the Buddhas realm. Avatamsaka (Flower Ornament) Sutra Neil Theise MD Departments of Pathology & Medicine Beth Israel Medical Center Albert Einstein College of Medicine New York City www.neiltheise.com

2. True Nature of Reality 3. Cognitive Contemplative True Nature of Reality 4. Cognitive Contemplative 5. Cognitive Contemplative Germs exist and cause disease 6. Cognitive Contemplative Germs exist and cause disease UV light leads to suntans and skin cancer 7. Cognitive Contemplative Germs exist and cause disease UV light leads to suntans and skin cancer Our galaxy is one of uncountable numbers in the universe 8. Cognitive Contemplative 9. Cognitive Contemplative Physical Nature of Reality Spiritual Nature of Reality 10. Cognitive Contemplative Physical Nature of Reality Spiritual Nature of Reality 1998 11. 12. 13. Lethal Irradiation Male bone marrow transplant F.I.S.H.for Y-Chromosome 14. 15. The Standard Paradigm: Restricted Plasticity 16. Irreversible gene restrictions Embryology & Adult Tissue Reconstitution Self renewal 17. BEWARE OF DOGMA 18. TheGreatStem Cell Debate 2001 19. Embryonic Stem Cells All three layers of the embryo: Mesoderm, Endoderm, Ectoderm 20. Embryonic Stem Cells All three layers of the embryo: Mesoderm:muscle, blood, bone Endoderm:visceral organs Ectoderm:brain, nerves, skin so. 21. Embryonic Stem Cells Can make everything! 22. Embryonic Stem Cells Can make everything, in order to: perform cell transplants create artificial organs (livers!) implant genes for gene therapies 23. Embryonic Stem Cells Can make everything! Adult Stem Cells Can make . . . ? 24. Sort PKH-bright Male Donor BM

Lin Deplete

Elutriate

PKH26 Label 48 Hours Transplantsinglecell into2 oFemale Recipient 1 oFemale Recipient 25. 26. 27. 28. 29. 30. 31. 32. Bone Marrow OneAdult Cell

Epithelia of

Liver

Lung

Gut, (Pancreas)

Skin, Hair follicles 33. MESODERM True clonality = True adult stem cell plasticity! OneAdult Cell ENDODERM ECTODERM 34. Pause 35. 36. What if gene restrictions are REVERSIBLE? 37. 38. Proof of Principle 39. 3 Principles of Plasticity Theise & Krause BCMD , May 2001 Leukemia,April Fools Day 2002 Comptes Rendus Biologies,December 2002 40. 1. Genomic Completeness 2. Cellular Uncertainty 3. Stochasticity ofCell Origins and Fates 41. 1. Genomic Completeness 2. Cellular Uncertainty 3. Stochasticity ofCell Origins and Fates 42. the internal and the external co-determine the cell. Richard Lewontin, 2000 43. 2 ndPrinciple: Cellular Uncertainty Any attempt to observe a cell alters the state of that cell at the time of characterization andpotentiallyalters the likelihood of subsequent differentiation events. 44. 2 ndPrinciple: Cellular Uncertainty Any attempt to observe a cell alters the state of that cell at the time of characterization and potentially alters the likelihood of subsequent differentiation events. ? 45. Meanwhile,back at the plasticity debates 46. Controversy!!! 47. trivial... vs. ROBUST!!! 48. Conversations with Jane Prophet New Media Artist and Professor, Interdisciplinary Studies University of Westminster, London UK SciArt Award, Wellcome Trust2002 49. Date: 9th May 2002Location: Neil's office, New York Jane says: Ideas about pathways are interesting. A lot of people who are involved in digital biology are interested in things like swarming people and so called soup organism behaviour. And one of the useful models to take forward is about ant colonies 50. Complex Adaptive Systems: 1,2 1 Lewin R, Complexity: Life at the Edge of Chaos. 2nd ed.Chicago IL: University of Chicago Press; 2002. 2 Johnson S, Emergence. New York NY: Scribner; 2001. 51. Complex Adaptive Systems: Interacting individuals that, fulfilling 4 criteria, organize themselves from the bottom up, into larger structures 52. Complex Adaptive Systems: Interacting individuals that, if they fulfill 4 criteria, organize themselves from the bottom up, into larger structures, whichappearplanned from the top, downward 53. Complex Adaptive Systems: Interacting individuals that, if they fulfill 4 criteria, organize themselves from the bottom up, into larger structures, which appear planned from the top, downward, BUT ARE NOT! 54. Complex Adaptive Systems: Interacting individuals that,if they fulfill 4 criteria, organize themselves from the bottom up, into larger structureswhich appear planned from the top, downward, BUT ARE NOT! These structures are referred to as emergent self-organization and are ADAPTIVE. 55. Complex Adaptive Systems: Rise and fall of economic markets Urban development Immune systems Beatlemania Rise and fall of civilizations Evolution and speciation 56. Complex Adaptive Systems: Rise and fall of economic markets Urban development Immune systems Beatlemania Rise and fall of civilizations Evolution and speciation Conciousness 57. Complex Adaptive Systems: Rise and fall of economic markets Urban development Immune systems Beatlemania Rise and fall of civilizations Evolution and speciation Conciousness Sesshin! 58.

Complex Adaptive Systems:

Numbers matter

59.

Complex Adaptive Systems:

Numbers matter

Negative feedback loops

60.

Complex Adaptive Systems:

Numbers matter

Negative feedback loops

Interactions are local without global sensing

61.

Complex Adaptive Systems:

Numbers matter

Negative feedback loops

Interactions are local without global sensing

Low level randomness

62.

Complex Adaptive Systems:

Numbers matter

Negative feedback loops

Interactions are local without global sensing

Quenched disorder

63. 64. 65. 66. Low level engraftmentis not only NOT trivial,but it is VITALliterally so. 1-3 1 Theise ND. Exp Hematology 2003 2 DInverno M, Theise ND. BCMD 2004 3 DInverno M, Theise ND, Prophet J. In: Potten C, Wilson J, Clarke R, Renahan A:Tissue stem cells: Biology and applications 67. Pause 68. Implications of Cell Lineages as Complex Adaptive Systems Mass extinctions. 69. order disorder chaos 70. disorder chaos complex adaptive systems order 71. Implications of Cell Lineages as Complex Adaptive Systems Mass extinctions, eg: ? Aplastic anemia ? Fulminant liver failure 72. Implications of Cell Lineages as Complex Adaptive Systems The price of adaptation,i.e. of LIFE, is DEATH 73. Implications of Cell Lineages as Complex Adaptive Systems Hierarchies of complex systems 74. 75. 76. 77. Implications of Cell Lineages as Complex Adaptive Systems Hierarchies of complex systems thingvs. phenomena depends on scale of observation 78. Communities Bodies Cells 79. e.g. cities, cultures, ecosystems, Gaia Bodies Cells 80. Communities Bodies Cells Biomolecules ? 81. Communities Bodies Cells ? 82. Communities Bodies Cells Biomolecules 83. Communities Bodies Cells Biomolecules More implications, of course. 84. 1. Genomic Completeness ? Cellular Uncertainty 3. Stochasticity ofCell Origins and Fates 85. Theise ND.Now you see it, now you dont. Nature , May 2005 Cell doctrine: modern biology and medicine see the cell as the fundamental building block of living organisms, but this concept breaks down at different perspectives and scales. Communities Bodies Cells Biomolecules 86. The validity of cell doctrine depends on the scale at which the body is observed Communities Bodies Cells Biomolecules 87. The validity of cell doctrine depends on the scale at which the body is observed. To limit ourselves to the perspective of this model may mean that explications of some bodily phenomena remain outside the capacity of modern biology Communities Bodies Cells Biomolecules 88. The validity of cell doctrine depends on the scale at which the body is observed. To limit ourselves to the perspective of this model may mean that explications of some bodily phenomena remain outside the capacity of modern biology e.g. Acupuncture Communities Bodies Cells Biomolecules 89. The validity of cell doctrine depends on the scale at which the body is observed. To limit ourselves to the perspective of this model may mean that explications of some bodily phenomena remain outside the capacity of modern biology. It is perhaps time to dethrone the doctrine of the cell, to allow alternative models of the body for study and exploitation in this new, postmodern era of biological investigation. Communities Bodies Cells Biomolecules 90. What kind of models? 91. for example, 2 models from Ancient Greece: Is the body made ofindivisible subunits or an endlessly divisible fluid 92. 93. 94. 95. 96. Models of the body areperspective/techniquedependent Look at it this way (cell membranes):the body is made of cells Look at it that way (organelles):the body is an endlessly divisible fluid 97. Models areperspective/techniquedependent Look at it this way (cell membranes):the body is made of cells Look at it that way (organelles): the body is an endlessly divisible fluid Yet another way (the genome): overlapping spatial/temporal fields of molecular organization 98. Pause 99. Still more implications of complexity in life 100. Communities Bodies Cells Biomolecules Atoms 101. Communities Bodies Cells Biomolecules Atoms Subatomic Particles 102. Communities Bodies Cells Biomolecules Atoms Subatomic Particles Strings (or whatever) 103. Communities Bodies Cells Biomolecules Atoms Subatomic Particles Strings (or whatever) The Quantum Foam 104. We dont liveinthe universe . . . 105. . . . wearethe universe 106. The Relative 107. The Absolute 108.

Implications ofEverything

as Complex Adaptive System

thingness is dependent on scale

109.

Implications ofEverything

as Complex Adaptive System

Emptiness of inherent existence

110.

Implications ofEverything

as Complex Adaptive System

Emptiness of inherent existence

2. Inevitable mass extinction

111.

Implications ofEverything

as Complex Adaptive System

Emptiness of inherent existence

2. Impermanence

112.

Implications of Everything

as Complex Adaptive System

Emptiness of inherent existence

2. Impermanence

3. Systems depend on EVERY member

113.

Implications of Everything

as Complex Adaptive System

Emptiness of inherent existence

2. Impermanence

3. Interdependence

114.

Implications of Everything

as Complex Adaptive System

Emptiness of inherent existence

2. Impermanence

3. Interdependence

4. The fact of emergence is predictable,

the nature of it is not.

115.

Implications of Everything

as Complex Adaptive System

Emptiness of inherent existence

2. Impermanence

3. Interdependence

4. Karmic law (cause and effect)

116. Implications of Everything as Complex Adaptive System Buddhist Metaphysics 117. Pause 118. Cognitive Contemplative 1998 119. Cognitive Contemplative 120. Cognitive Contemplative One True Nature of Reality, Not Two 121. Diane Krause MD PhD Saul Sharkis MD PhD,Michael Collector Octavian Henegariu MD Sonya Hwang MD, Rebekah Gardner Sarah Neutzel Single cell multiorgan plasticity 122. Cell Team Jane Prophet Mark DInverno Rob Saunders Peter Ride Neil Theise Discussions were part of the production of "Cell",a collaboration across art and sciencefunded by a Wellcome Trust SciArt Awardand an award from Future Physical."Cell" is coordinated by Peter Rideand is a DA2 Digital Arts Agency production. 123. my Zen teacher, Roshi Pat Enkyo Ohara and of course 124.