The document discusses stem cell plasticity and complexity theory from multiple perspectives. It proposes that cell lineages and bodies can be understood as complex adaptive systems with hierarchical organization from the quantum to the macro scale. Understanding bodies in this way allows for alternative models beyond the traditional cell doctrine and may provide insights into phenomena like acupuncture.

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. “ Thinking is better than knowing… Goethe – “Maxims”

3. “ Thinking is better than knowing, but LOOKING is even better!” Goethe – “Maxims”

4. Haruna et al. Hepatology 1996; 23: 476

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.

15. The Normal Liver Lobule:

16. The NEW Normal Liver Lobule:

20. Lethal Irradiation Male Bone Marrow Transplant FISH for Y-Chromosome Theise & Krause, et al. Hepatology Jan 2000

31. True clonality = True adult stem cell plasticity! MESODERM ENDODERM ECTODERM One Adult Cell

32. The Standard Paradigm: Restricted Plasticity

33. Irreversible gene restrictions Embryology & Adult Tissue Reconstitution Self renewal

34. What if gene restrictions are REVERSIBLE?

36. Proof of Principle

37. BEWARE OF DOGMA

38. 3 Principles of Plasticity Theise & Krause BCMD , May 2001 Leukemia, April Fool’s Day 2002 Comptes Rendus Biologies, December 2002

39. 1. Genomic Completeness 2. Cellular Uncertainty 3. Stochasticity of Cell Origins and Fates

40. 1. Genomic Completeness 2. Cellular Uncertainty 3. Stochasticity of Cell Origins and Fates

41. “… the internal and the external co-determine the cell.” Richard Lewontin, 2000

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.

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. ?

44. Meanwhile, back at the plasticity debates…

45. Controversy!!!

46. trivial... vs. ROBUST!!!

47. Conversations with Jane Prophet New Media Artist and Professor, Interdisciplinary Studies University of Westminster, London UK SciArt Award, Wellcome Trust 2002

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…”

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.

50. … Complex Adaptive Systems: Interacting individuals that, if they fulfill 4 criteria, organize themselves from the bottom up, into larger structures

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 ,

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!

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

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?

55. Complex Systems Real world

56. Complex Systems Real Virtual

57. Complex Systems Real Virtual

58. Complex Adaptive Systems: Rise and fall of economic markets Urban development Beatlemania Rise and fall of civilizations Evolution and speciation Immunology

59. Complex Adaptive Systems: Rise and fall of economic markets Urban development Beatlemania Rise and fall of civilizations Evolution and speciation Immunology Conciousness

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

69. Implications of Cell Lineages as Complex Adaptive Systems Mass extinctions.

70. order disorder “ chaos”

71. disorder “ chaos” complex adaptive systems order

72. Implications of Cell Lineages as Complex Adaptive Systems Mass extinctions, eg: ? Aplastic anemia ? Fulminant liver failure

73. Implications of Cell Lineages as Complex Adaptive Systems The price of adaptation, i.e. of LIFE, is DEATH

74. Implications of Cell Lineages as Complex Adaptive Systems Hierarchies of complex systems…

78. Implications of Cell Lineages as Complex Adaptive Systems Hierarchies of complex systems… thing vs. phenomena depends on scale of observation

80. Communities Bodies Cells

81. e.g. cities, cultures, ecosystems, Gaia Bodies Cells

82. Communities Bodies Cells Biomolecules ?

83. Communities Bodies Cells Biomolecules Toshio Yanagida & Company

84. Communities Bodies Cells Biomolecules More implications, of course.

85. 1. Genomic Completeness ? Cellular Uncertainty 3. Stochasticity of Cell Origins and Fates

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

87. “ The validity of cell doctrine depends on the scale at which the body is observed… 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… 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… e.g. Acupuncture Communities Bodies Cells Biomolecules

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

91. What kind of models?

92. for example, 2 models from Ancient Greece: Is the body made of… indivisible subunits or an endlessly divisible fluid

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

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.

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

100. Communities Bodies Cells Biomolecules Atoms

101. Communities Bodies Cells Biomolecules Atoms We are walking, talking Earth…

102. Communities Bodies Cells Biomolecules Atoms Subatomic Particles

103. Put group portrait from menla conference HERE

104. Beyond cell doctrine: Complexity thery informs alternate models of the bdy For cross cultural dialogue Neil D. Theise www.neiltheise.com

105. Macroscopic body Microscopic body Nanoscopic body Quantum body

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

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?

108. Macroscopic body Microscopic body Nanoscopic body Quantum body Coarse Body ? Energy Body ? Subtle Body ? Indo-Tibetan Medicine/Physiology

109. Macroscopic body Microscopic body Nanoscopic body Quantum body Coarse Body ? Energy Body ? Subtle Body ? Indo-Tibetan Medicine/Physiology

110. Communities Bodies Cells Biomolecules Atoms Subatomic Particles Strings (or whatever)

111. Communities Bodies Cells Biomolecules Atoms Subatomic Particles Strings (or whatever) The Quantum Foam

112. We don’t live in the universe . . .

113. . . . we are the universe

114. The Relative

115. The Absolute

116. Implications of Everything as Hierarchical Complex Systems Buddhist Metaphysics

117. Implications of Everything as Hierarchical Complex Systems Jewish Mysticism

118. Implications of Everything as Complex Adaptive Systems Hindu Mysticism