1. Stem Cells, Complexity, and the Science of Being Neil Theise MDDepartments of Pathology & Medicine Beth Israel Medical Center Albert Einstein College of Medicine New York Citywww.neiltheise.com

2. 1o Female RecipientMale Donor BM 48 Hours PKH26Lin Deplete Label Elutriate Sort PKH-brightTransplant single cell into 2o Female Recipient 3. Bone MarrowOneAdult CellEpithelia of Skin, Hair follicles Liver Lung Gut, (Pancreas) 4. MESODERMOneAdult Cell ENDODERMECTODERMTrue clonality = True adult stem cell plasticity! 5. The Standard Paradigm:Restricted Plasticity 6. Embryology &Adult Tissue ReconstitutionSelf renewalIrreversible gene restrictions 7. BEWAREOFDOGMA 8. What if gene restrictionsare REVERSIBLE? 9. 3 Principles of Plasticity Theise & Krause BCMD, May 2001Leukemia, April Fools Day 2002Comptes Rendus Biologies, December 2002 10. 1. Genomic Completeness2. Cellular Uncertainty3. Stochasticity of Cell Origins and Fates 11. 1. Genomic Completeness2. Cellular Uncertainty3. Stochasticity of Cell Origins and Fates 12. the internal and the external co-determine the cell.Richard Lewontin, 2000 13. 2nd Principle:Cellular UncertaintyAny 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. 14. 2nd Principle:Cellular UncertaintyAny 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.? 15. Meanwhile,back at the plasticity debates 16. Controversy!!! 17. trivial...vs.ROBUST!!! 18. Conversations with Jane ProphetNew Media Artist and Professor, Interdisciplinary StudiesUniversity of Westminster, London UKSciArt Award, Wellcome Trust 2002 19. Date: 9th May 2002Location: Neils office, New YorkJane says: Ideas about pathways are interesting. A lot of people who are involved in digital biology are interested in things like swarming people and socalled soup organism behaviour. And one of the useful models to take forward is about ant colonies 20. Complex Adaptive Systems:1,21Lewin R, Complexity: Life at the Edge of Chaos. 2nd ed. Chicago IL: University of Chicago Press; 2002.2Johnson S, Emergence. New York NY: Scribner; 2001. 21. Complex Adaptive Systems: Interacting individuals that, if they fulfill 4 criteria,organize themselves from the bottom up,into larger structures 22. 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 23. 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! 24. 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 asemergent self-organization and are ADAPTIVE. 25. Complex Adaptive Systems:Rise and fall of economic markets Urban developmentImmune systemsBeatlemania Rise and fall of civilizationsEvolution and speciation 26. Complex Adaptive Systems:Rise and fall of economic markets Urban developmentImmune systemsBeatlemania Rise and fall of civilizationsEvolution and speciation Conciousness 27. Complex Adaptive Systems: Numbers matter 28. Complex Adaptive Systems: Numbers matter Negative feedback loops 29. Complex Adaptive Systems: Numbers matter Negative feedback loops Interactions are local without global sensing 30. Complex Adaptive Systems: Numbers matter Negative feedback loops Interactions are local without global sensing Low level randomness 31. Complex Adaptive Systems: Numbers matter Negative feedback loops Interactions are local without global sensing Quenched disorder 32. Low level engraftmentis not only NOT trivial,but it is VITAL literally so.1-31Theise ND. Exp Hematology 20032DInverno M, Theise ND. BCMD 20043DInverno M, Theise ND, Prophet J. In: Potten C, Wilson J, Clarke R, Renahan A: Tissue stem cells: Biology and applications 33. Implications of Cell Lineagesas Complex Adaptive Systems Mass extinctions. 34. chaosdisorder order 35. chaosdisorder complex adaptivesystems order 36. Implications of Cell Lineagesas Complex Adaptive Systems Mass extinctions, eg: ? Aplastic anemia? Fulminant liver failure 37. Implications of Cell Lineagesas Complex Adaptive SystemsThe price of adaptation,i.e. of LIFE, is DEATH 38. Implications of Cell Lineagesas Complex Adaptive SystemsHierarchies of complex systems 39. Implications of Cell Lineagesas Complex Adaptive SystemsHierarchies of complex systems thing vs. phenomenadepends on scale of observation 40. CommunitiesBodies Cells 41. e.g. cities, cultures, ecosystems, GaiaBodies Cells 42. CommunitiesBodies Cells? 43. Communities BodiesCellsBiomolecules ? 44. Communities BodiesCellsBiomolecules 45. CommunitiesBodies Cells BiomoleculesMore implications, of course. 46. 1. Genomic Completeness? Cellular Uncertainty3. Stochasticity of Cell Origins and Fates 47. Communities BodiesCellsBiomoleculesTheise ND.Now you see it, now you dont.Nature, May 2005Cell doctrine: modern biology and medicine see thecell as the fundamental building block of livingorganisms, but this concept breaks down at differentperspectives and scales. 48. Communities BodiesCellsBiomoleculesThe validity of cell doctrine depends on the scale atwhich the body is observed 49. Communities BodiesCellsBiomoleculesThe validity of cell doctrine depends on the scale atwhich the body is observed. To limit ourselves to theperspective of this model may mean that explications ofsome bodily phenomena remain outside the capacity ofmodern biology 50. Communities BodiesCellsBiomoleculesThe validity of cell doctrine depends on the scale atwhich the body is observed. To limit ourselves to theperspective of this model may mean that explications ofsome bodily phenomena remain outside the capacity ofmodern biologye.g. Acupuncture 51. Communities BodiesCellsBiomoleculesThe validity of cell doctrine depends on the scale atwhich the body is observed. To limit ourselves to theperspective of this model may mean that explications ofsome bodily phenomena remain outside the capacity ofmodern biology. It is perhaps time to dethrone thedoctrine of the cell, to allow alternative models of thebody for study and exploitation in this new, postmodernera of biological investigation. 52. What kind of models? 53. for example,2 models from Ancient Greece:Is the body made ofindivisible subunits or an endlessly divisible fluid 54. Models of the body are perspective/technique dependent Look at it this way (cell membranes): the body is made of cellsLook at it that way (organelles): the body is an endlessly divisible fluid 55. Models are perspective/technique dependentLook at it this way (cell membranes):the body is made of cells Look at it that way (organelles):the body is an endlessly divisible fluidYet another way (the genome): overlapping spatial/temporal fields of molecular organization 56. Still more implications of complexity in life 57. Communities BodiesCellsBiomolecules Atoms 58. Communities BodiesCellsBiomolecules Atoms 59. Communities BodiesCellsBiomolecules Atoms 60. CommunitiesBodies Cells BiomoleculesAtomsWe are walking, talking Earth 61. Communities BodiesCellsBiomoleculesAtomsSubatomic Particles 62. Communities BodiesCellsBiomolecules AtomsSubatomic ParticlesStrings (or whatever) 63. Communities BodiesCellsBiomolecules AtomsSubatomic ParticlesStrings (or whatever)The Quantum Foam 64. We dont live in the universe . . . 65. . . . we are the universe 66. Implications of Everything as Complex Adaptive System Science-Metaphysics Interface Complementarity Consciousness Studies 67. Implications of Everything as Complex Adaptive System Science-Metaphysics Interface Complementarity Consciousness Studies 68. The Relative 69. The Absolute 70. Implications of Everythingas Complex Adaptive System3. thingness is dependent on scale 71. Implications of Everything as Complex Adaptive System3. Emptiness of inherent existence 72. Implications of Everything as Complex Adaptive System3. Emptiness of inherent existence 2. Inevitable mass extinction 73. Implications of Everything as Complex Adaptive System3. Emptiness of inherent existence 2. Impermanence 74. Implications of Everythingas Complex Adaptive System 3. Emptiness of inherent existence2. Impermanence3. Systems depend on EVERY member 75. Implications of Everything as Complex Adaptive System3. Emptiness of inherent existence 2. Impermanence3. Interdependence 76. Implications of Everythingas Complex Adaptive System 3. Emptiness of inherent existence2. Impermanence 3. Interdependence4. The fact of emergence is predictable,the nature of it is not. 77. Implications of Everything as Complex Adaptive System3. Emptiness of inherent existence 2. Impermanence3. Interdependence 4. Karmic law (cause and effect) 78. Implications of Everythingas Complex Adaptive System Buddhist Metaphysics 79. Implications of Everythingas Hierarchical Complex Systems Jewish Mysticism 80. Implications of Everythingas Complex Adaptive SystemsHindu Mysticism 81. Implications of Everything as Complex Adaptive System Science-Metaphysics Interface Biological Complementarity Consciousness Studies 82. Bohr, Delbruck, Menas Kafatos 83. Implications of Everything as Complex Adaptive System Science-Metaphysics Interface Complementarity Consciousness Studies 84. HUMBERT R. MATURANA and FRANCISCO J. VARELAAll living systems are autopoietic systems.AUTOPOIESIS AND COGNITION The Realization of the LivingWith a preface on Autopoiesisby SIR STAFFORD BEERS1. Boundary: open to energy but closed to foreign materials i.e. is semi-porous. 85. HUMBERT R. MATURANA and FRANCISCO J. VARELAAll living systems are autopoietic systems.AUTOPOIESIS AND COGNITION The Realization of the LivingWith a preface on Autopoiesisby SIR STAFFORD BEERS1. Boundary: open to energy but closed to foreign materials i.e. is semi-porous.2. Processes: the boundary is the being and the processes are the doing of a living system. 86. HUMBERT R. MATURANA and FRANCISCO J. VARELAAll living systems are autopoietic systems.AUTOPOIESIS AND COGNITION The Realization of the LivingWith a preface on Autopoiesisby SIR STAFFORD BEERS1. Boundary: open to energy but closed to foreign materials i.e. is semi-porous.2. Processes: the boundary is the being and the processes are the doing of a living system.3. Nervous System: the connection between external events and the internal processes of the living system. 87. HUMBERT R. MATURANA and FRANCISCO J. VARELAAll living systems are autopoietic systems.AUTOPOIESIS AND COGNITION The Realization of the LivingWith a preface on Autopoiesisby SIR STAFFORD BEERS1. Boundary: open to energy but closed to foreign materials i.e. is semi-porous.2. Processes: the boundary is the being and the processes are the doing of a living system.3. Nervous System: the connection between external events and the internal processes of the living system.4. Communication Channels: between the living system and its external environment. 88. HUMBERT R. MATURANA and FRANCISCO J. VARELA All living systems are cognitive systems.AUTOPOIESIS AND COGNITION The Realization of the LivingWith a preface on Autopoiesisby SIR STAFFORD BEERS 89. HUMBERT R. MATURANA and FRANCISCO J. VARELA All living systems are cognitive systems.AUTOPOIESIS AND COGNITION The Realization of the LivingWith a preface on Autopoiesisby SIR STAFFORD BEERS 90. All living systems are cognitive systems.Conciousness Sense Making Sentience 91. Theyve found that some of the key molecularbuilding blocks of neurons predate even the firstmulticellular organisms. By looking down the treeof life, they are concluding that assembling thesecomponents into a cell a modern neuroscientistwould recognize as a neuron probably happenedvery early in animal evolution, more than 600million years ago. Most scientists agree thatcircuits of interconnected neurons probably arosesoon thereafter, first as diffuse webs and later as acentralized brain and nerves. G. Miller, Science, 2009 92. sg s nesakin ce ciouse M tienCo nSen SenCommunities BodiesCellsBiomolecules AtomsSubatomic ParticlesStrings (or whatever) 93. sg s nesakin ce ciouse M tienCo nSen SenCommunities BodiesCellsBiomoleculesOnly living(biological) Atomssystems??? Subatomic ParticlesStrings (or whatever) 94. sg s nesakin ce ciouse M tienCo nSen SenCommunities BodiesCellsBiomolecules ? AtomsSubatomic ParticlesStrings (or whatever) 95. Biomolecules!!! 96. Only biomolecules??? 97. Atoms!!! 98. Only atoms??? 99. Subatomic particles!!! 10-18mStrings 10-35m (orwhatever) 100. Conclusion:While one may argue that sense makingand therefore some form of conciousness islimited, extending downward in scale onlyto the smallest, autopoietic elements of life namely the cell a complexity analysis ofthe universe (as a unified, self-organizingand emergent system) reveals that theuniverse is sentient throughout; thatsentience is inherent and universal in thestructures of existence. 101. Conclusion:While one may argue that sense makingand therefore some form of conciousness islimited, extending downward in scale onlyto the smallest, autopoietic elements of life namely the cell a complexity analysis ofthe universe (as a unified, self-organizingand emergent system) reveals that theuniverse is sentient throughout; thatsentience is inherent and universal in thestructures of existence. 102. Conclusion:While one may argue that sense makingand therefore some form of conciousness islimited, extending downward in scale onlyto the smallest, autopoietic elements of life namely the cell a complexity analysis ofthe universe (as a unified, self-organizingand emergent system) reveals that theuniverse is sentient throughout; thatsentience is inherent and universal in thestructures of existence. 103. Conclusion:While one may argue that sense makingand therefore some form of conciousness islimited, extending downward in scale onlyto the smallest, autopoietic elements of life namely the cell a complexity analysis ofthe universe (as a unified, self-organizingand emergent system) reveals that theuniverse is sentient throughout; thatsentience is inherent and universal in thestructures of existence. 104. sg s nesakin ce ciouse M tienCo nSen SenCommunities BodiesCellsBiomolecules?? AtomsSubatomic ParticlesStrings (or whatever) 105. Single cell multiorgan plasticityDiane Krause MD PhDSaul Sharkis MD PhD, Michael Collector Octavian Henegariu MDSonya Hwang MD, Rebekah Gardner Sarah Neutzel 106. Cell TeamJane Prophet Mark DInverno Rob Saunders Peter Ride Neil TheiseDiscussions were part of the production of "Cell", a collaboration across art and science funded by a Wellcome Trust SciArt Awardand an award from Future Physical. "Cell" is coordinated by Peter Rideand is a DA2 Digital Arts Agency production.