Touro 2010

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Touro 2010

  1. 1. Who Are We? Stem Cells, Complexity and the Science of Being Neil Theise MD Departments of Pathology & Medicine Beth Israel Medical Center – Albert Einstein College of Medicine New York City www.neiltheise.com
  2. 2. “ Thinking is better than knowing… Goethe – “Maxims”
  3. 3. “ Thinking is better than knowing, but LOOKING is even better!” Goethe – “Maxims”
  4. 4. Haruna et al. Hepatology 1996; 23: 476
  5. 13. Aleta and James Crawford for Theise et al., Hepatology. 1999; 30: 1425. Definitions according to: Roskams, Theise et al., Hepatology 2004; 39: 1739-45.
  6. 15. The Normal Liver Lobule:
  7. 16. The NEW Normal Liver Lobule:
  8. 20. Lethal Irradiation Male Bone Marrow Transplant FISH for Y-Chromosome Theise & Krause, et al. Hepatology Jan 2000
  9. 22. Sort PKH-bright Male Donor BM <ul><li>Lin Deplete </li></ul><ul><li>Elutriate </li></ul>PKH26 Label 48 Hours Transplant single cell into 2 o Female Recipient 1 o Female Recipient
  10. 30. Bone Marrow One Adult Cell <ul><li>Epithelia of </li></ul><ul><li>Liver </li></ul><ul><li>Lung </li></ul><ul><li>Gut, (Pancreas) </li></ul>Skin, Hair follicles
  11. 31. True clonality = True adult stem cell plasticity! MESODERM ENDODERM ECTODERM One Adult Cell
  12. 32. The Standard Paradigm: Restricted Plasticity
  13. 33. Irreversible gene restrictions Embryology & Adult Tissue Reconstitution Self renewal
  14. 34. What if gene restrictions are REVERSIBLE?
  15. 36. Proof of Principle
  16. 37. BEWARE OF DOGMA
  17. 38. 3 Principles of Plasticity Theise & Krause BCMD , May 2001 Leukemia, April Fool’s Day 2002 Comptes Rendus Biologies, December 2002
  18. 39. 1. Genomic Completeness 2. Cellular Uncertainty 3. Stochasticity of Cell Origins and Fates
  19. 40. 1. Genomic Completeness 2. Cellular Uncertainty 3. Stochasticity of Cell Origins and Fates
  20. 41. “… the internal and the external co-determine the cell.” Richard Lewontin, 2000
  21. 42. 2 nd Principle: 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.
  22. 43. 2 nd Principle: 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. ?
  23. 44. Meanwhile, back at the plasticity debates…
  24. 45. Controversy!!!
  25. 46. trivial... vs. ROBUST!!!
  26. 47. Conversations with Jane Prophet New Media Artist and Professor, Interdisciplinary Studies University of Westminster, London UK SciArt Award, Wellcome Trust 2002
  27. 48. Date: 9th May 2002 Location: 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…”
  28. 49. 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.
  29. 50. … Complex Adaptive Systems: Interacting individuals that, if they fulfill 4 criteria, organize themselves from the bottom up, into larger structures
  30. 51. Complex Adaptive Systems: Interacting individuals that, if they fulfill 4 criteria, organize themselves from the bottom up, into larger structures that appear planned from the top, downward ,
  31. 52. Complex Adaptive Systems: Interacting individuals that, if they fulfill 4 criteria, organize themselves from the bottom up, into larger structures that appear planned from the top, downward, BUT ARE NOT!
  32. 53. Complex Adaptive Systems: Interacting individuals that, if they fulfill 4 criteria, organize themselves from the bottom up, into larger structures that appear planned from the top, downward, BUT ARE NOT! These structures are ADAPTIVE and are referred to as emergent self-organization
  33. 54. Complex Adaptive Systems: Interacting individuals that, if they fulfill 4 criteria, organize themselves from the bottom up, into larger structures that appear planned from the top, downward, BUT ARE NOT! How do we know?
  34. 55. Complex Systems Real world
  35. 56. Complex Systems Real Virtual
  36. 57. Complex Systems Real Virtual
  37. 58. Complex Adaptive Systems: Rise and fall of economic markets Urban development Beatlemania Rise and fall of civilizations Evolution and speciation Immunology
  38. 59. Complex Adaptive Systems: Rise and fall of economic markets Urban development Beatlemania Rise and fall of civilizations Evolution and speciation Immunology Conciousness
  39. 60. <ul><li>Complex Adaptive Systems: </li></ul><ul><li>Numbers matter </li></ul>
  40. 61. <ul><li>Complex Adaptive Systems: </li></ul><ul><li>Numbers matter </li></ul><ul><li>Negative feedback loops </li></ul>
  41. 62. <ul><li>Complex Adaptive Systems: </li></ul><ul><li>Numbers matter </li></ul><ul><li>Negative feedback loops </li></ul><ul><li>Interactions are local without global sensing </li></ul>
  42. 63. <ul><li>Complex Adaptive Systems: </li></ul><ul><li>Numbers matter </li></ul><ul><li>Negative feedback loops </li></ul><ul><li>Interactions are local without global sensing </li></ul><ul><li>Low level randomness </li></ul>
  43. 64. <ul><li>Complex Adaptive Systems: </li></ul><ul><li>Numbers matter </li></ul><ul><li>Negative feedback loops </li></ul><ul><li>Interactions are local without global sensing </li></ul><ul><li>“ Quenched disorder” </li></ul>
  44. 68. Low level engraftment is not only NOT trivial, but it is VITAL – literally so. 1-3 1 Theise ND. Exp Hematology 2003 2 D’Inverno M, Theise ND. BCMD 2004 3 D’Inverno M, Theise ND, Prophet J. In: Potten C, Wilson J, Clarke R, Renahan A: Tissue stem cells: Biology and applications
  45. 69. Implications of Cell Lineages as Complex Adaptive Systems Mass extinctions.
  46. 70. order disorder “ chaos”
  47. 71. disorder “ chaos” complex adaptive systems order
  48. 72. Implications of Cell Lineages as Complex Adaptive Systems Mass extinctions, eg: ? Aplastic anemia ? Fulminant liver failure
  49. 73. Implications of Cell Lineages as Complex Adaptive Systems The price of adaptation, i.e. of LIFE, is DEATH
  50. 74. Implications of Cell Lineages as Complex Adaptive Systems Hierarchies of complex systems…
  51. 78. Implications of Cell Lineages as Complex Adaptive Systems Hierarchies of complex systems… thing vs. phenomena depends on scale of observation
  52. 80. Communities Bodies Cells
  53. 81. e.g. cities, cultures, ecosystems, Gaia Bodies Cells
  54. 82. Communities Bodies Cells Biomolecules ?
  55. 83. Communities Bodies Cells Biomolecules Toshio Yanagida & Company
  56. 84. Communities Bodies Cells Biomolecules More implications, of course.
  57. 85. 1. Genomic Completeness ? Cellular Uncertainty 3. Stochasticity of Cell Origins and Fates
  58. 86. Theise ND. Now you see it, now you don’t. 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
  59. 87. “ The validity of cell doctrine depends on the scale at which the body is observed… Communities Bodies Cells Biomolecules
  60. 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… Communities Bodies Cells Biomolecules
  61. 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… e.g. Acupuncture Communities Bodies Cells Biomolecules
  62. 90. “ 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
  63. 91. What kind of models?
  64. 92. for example, 2 models from Ancient Greece: Is the body made of… indivisible subunits or an endlessly divisible fluid
  65. 97. Models of the body are perspective/technique dependent 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
  66. 98. A study of acupuncture mechanism by magnetic resonance elastography Chan QC, Li G, Ehman RL, Rossman PJ, Cao G, Li R, Yang ES Conf Proc IEEE Eng Med Biol Soc. 2004;2:1022-4.
  67. 99. Models are perspective/technique dependent 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
  68. 100. Communities Bodies Cells Biomolecules Atoms
  69. 101. Communities Bodies Cells Biomolecules Atoms We are walking, talking Earth…
  70. 102. Communities Bodies Cells Biomolecules Atoms Subatomic Particles
  71. 103. Put group portrait from menla conference HERE
  72. 104. Beyond cell doctrine: Complexity thery informs alternate models of the bdy For cross cultural dialogue Neil D. Theise www.neiltheise.com
  73. 105. Macroscopic body Microscopic body Nanoscopic body Quantum body
  74. 106. Macroscopic body Microscopic body Nanoscopic body Quantum body e.g. physical therapy surgery e.g. cell therapies e.g. molecular medicine antibiotics e.g. electromagnetics
  75. 107. Macroscopic body Microscopic body Nanoscopic body Quantum body e.g. yoga tai chi e.g. acupuncture? e.g. traditional remedies e.g. energy healing? meditation?
  76. 108. Macroscopic body Microscopic body Nanoscopic body Quantum body Coarse Body ? Energy Body ? Subtle Body ? Indo-Tibetan Medicine/Physiology
  77. 109. Macroscopic body Microscopic body Nanoscopic body Quantum body Coarse Body ? Energy Body ? Subtle Body ? Indo-Tibetan Medicine/Physiology
  78. 110. Communities Bodies Cells Biomolecules Atoms Subatomic Particles Strings (or whatever)
  79. 111. Communities Bodies Cells Biomolecules Atoms Subatomic Particles Strings (or whatever) The Quantum Foam
  80. 112. We don’t live in the universe . . .
  81. 113. . . . we are the universe
  82. 114. The Relative
  83. 115. The Absolute
  84. 116. Implications of Everything as Hierarchical Complex Systems Buddhist Metaphysics
  85. 117. Implications of Everything as Hierarchical Complex Systems Jewish Mysticism
  86. 118. Implications of Everything as Complex Adaptive Systems Hindu Mysticism
  87. 119. <ul><li>Marrow-Liver Plasticity </li></ul><ul><ul><li>Diane Krause </li></ul></ul><ul><ul><li>James Crawford </li></ul></ul><ul><ul><li>Tavi Henegariu </li></ul></ul><ul><ul><li>Romil Saxena </li></ul></ul><ul><ul><li>Sunil Badve </li></ul></ul><ul><li>Single Cell Plasticity </li></ul><ul><ul><li>Diane Krause </li></ul></ul><ul><ul><li>Michael Collector </li></ul></ul><ul><ul><li>Saul Sharkis </li></ul></ul><ul><ul><li>Tavi Henegariu </li></ul></ul><ul><li>Canals of Hering </li></ul><ul><ul><li>James Crawford </li></ul></ul><ul><ul><li>Romil Saxena </li></ul></ul><ul><ul><li>Bernard Portmann </li></ul></ul><ul><ul><li>Swan Thung </li></ul></ul><ul><li>Agent-based modeling </li></ul><ul><li>of stem cell systems </li></ul><ul><ul><li>Mark D’Inverno </li></ul></ul><ul><ul><li>Rob Saunders </li></ul></ul><ul><ul><li>Jane Prophet </li></ul></ul><ul><ul><li>Peter Ride </li></ul></ul>

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