Talk for UBC students 3/2012

1. 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. 1o Female Recipient
Male Donor BM
48 Hours
PKH26
Lin Deplete Label
Elutriate
Sort PKH-bright
Transplant single cell into
2o Female Recipient

10. Bone Marrow
One
Adult Cell
Epithelia of Skin, Hair follicles
• Liver
• Lung
• Gut, (Pancreas)

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

12. The Standard Paradigm:
Restricted Plasticity

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

14. BEWARE
OF
DOGMA

16. What if gene restrictions
are REVERSIBLE?

19. 3 Principles of Plasticity
Theise & Krause
BCMD, May 2001
Leukemia, April Fool’s Day 2002
Comptes Rendus Biologies, December 2002

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

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

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

23. 2nd 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.

24. 2nd 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.
?

25. Meanwhile,
back at the plasticity debates…

26. Controversy!!!

27. trivial...
vs.
ROBUST!!!

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

29. 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…”

30. 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.

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

32. 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…

33. 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!

34. 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!
These structures are referred to as
“emergent self-organization”
and are ADAPTIVE.

35. Complex Adaptive Systems:
Rise and fall of economic markets
Urban development
Immune systems
Beatlemania
Rise and fall of civilizations
Evolution and speciation

36. Complex Adaptive Systems:
Rise and fall of economic markets
Urban development
Immune systems
Beatlemania
Rise and fall of civilizations
Evolution and speciation
Conciousness

37. Complex Adaptive Systems:
• Numbers matter

38. Complex Adaptive Systems:
• Numbers matter
• Negative feedback loops

39. Complex Adaptive Systems:
• Numbers matter
• Negative feedback loops
• Interactions are local without global sensing

40. Complex Adaptive Systems:
• Numbers matter
• Negative feedback loops
• Interactions are local without global sensing
• Low level randomness

41. Complex Adaptive Systems:
• Numbers matter
• Negative feedback loops
• Interactions are local without global sensing
• “Quenched disorder”

45. 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

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

47. “chaos”
disorder
order

48. “chaos”
disorder
complex
adaptive
systems
order

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

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

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

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

57. Communities
Bodies
Cells

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

59. Communities
Bodies
Cells
?

60. Communities
Bodies
Cells
Biomolecules ?

61. Communities
Bodies
Cells
Biomolecules

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

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

64. Communities
Bodies
Cells
Biomolecules
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.”

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

66. Communities
Bodies
Cells
Biomolecules
“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…

67. Communities
Bodies
Cells
Biomolecules
“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

68. Communities
Bodies
Cells
Biomolecules
“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.”

69. What kind of models?

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

75. 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

76. 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

77. Still more implications of
complexity in life…

78. Communities
Bodies
Cells
Biomolecules
Atoms

79. Communities
Bodies
Cells
Biomolecules
Atoms

80. Communities
Bodies
Cells
Biomolecules
Atoms

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

82. Communities
Bodies
Cells
Biomolecules
Atoms
Subatomic Particles

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

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

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

86. . . . we are the universe

87. Implications of Everything
as Complex Adaptive System
 Science-Metaphysics Interface
 Complementarity
 Consciousness Studies

88. Implications of Everything
as Complex Adaptive System
 Science-Metaphysics Interface
 Complementarity
 Consciousness Studies

89. The Relative

90. The Absolute

91. Implications of Everything
as Complex Adaptive System
3. “thingness” is dependent on scale

92. Implications of Everything
as Complex Adaptive System
3. Emptiness of inherent existence

93. Implications of Everything
as Complex Adaptive System
3. Emptiness of inherent existence
2. Inevitable mass extinction

94. Implications of Everything
as Complex Adaptive System
3. Emptiness of inherent existence
2. Impermanence

95. Implications of Everything
as Complex Adaptive System
3. Emptiness of inherent existence
2. Impermanence
3. Systems depend on EVERY member

96. Implications of Everything
as Complex Adaptive System
3. Emptiness of inherent existence
2. Impermanence
3. Interdependence

97. Implications of Everything
as Complex Adaptive System
3. Emptiness of inherent existence
2. Impermanence
3. Interdependence
4. The fact of emergence is predictable,
the nature of it is not.

98. Implications of Everything
as Complex Adaptive System
3. Emptiness of inherent existence
2. Impermanence
3. Interdependence
4. Karmic law (cause and effect)

99. Implications of Everything
as Complex Adaptive System
Buddhist Metaphysics

100. Implications of Everything
as Hierarchical Complex Systems
Jewish Mysticism

101. Implications of Everything
as Complex Adaptive Systems
Hindu Mysticism

102. Implications of Everything
as Complex Adaptive System
 Science-Metaphysics Interface
 Biological Complementarity
 Consciousness Studies

103. Bohr, Delbruck, Menas Kafatos

106. Implications of Everything
as Complex Adaptive System
 Science-Metaphysics Interface
 Complementarity
 Consciousness Studies

107. HUMBERT R. MATURANA and FRANCISCO J. VARELA All living systems are autopoietic systems.
AUTOPOIESIS
AND
COGNITION
The Realization of the Living
With a preface on “Autopoiesis”
by
SIR STAFFORD BEERS
1. Boundary: open to energy but closed to foreign
materials – i.e. is semi-porous.

108. HUMBERT R. MATURANA and FRANCISCO J. VARELA All living systems are autopoietic systems.
AUTOPOIESIS
AND
COGNITION
The Realization of the Living
With a preface on “Autopoiesis”
by
SIR STAFFORD BEERS
1. 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.

109. HUMBERT R. MATURANA and FRANCISCO J. VARELA All living systems are autopoietic systems.
AUTOPOIESIS
AND
COGNITION
The Realization of the Living
With a preface on “Autopoiesis”
by
SIR STAFFORD BEERS
1. 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.

110. HUMBERT R. MATURANA and FRANCISCO J. VARELA All living systems are autopoietic systems.
AUTOPOIESIS
AND
COGNITION
The Realization of the Living
With a preface on “Autopoiesis”
by
SIR STAFFORD BEERS
1. 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.

111. HUMBERT R. MATURANA and FRANCISCO J. VARELA All living systems are cognitive systems.
AUTOPOIESIS
AND
COGNITION
The Realization of the Living
With a preface on “Autopoiesis”
by
SIR STAFFORD BEERS

112. HUMBERT R. MATURANA and FRANCISCO J. VARELA All living systems are cognitive systems.
AUTOPOIESIS
AND
COGNITION
The Realization of the Living
With a preface on “Autopoiesis”
by
SIR STAFFORD BEERS

113. All living systems are cognitive systems.
Conciousness <> Sense Making <> Sentience

114. They’ve found that some of the key molecular
building blocks of neurons predate even the first
multicellular organisms. By looking down the tree
of life, they are concluding that assembling these
components into a cell a modern neuroscientist
would recognize as a neuron probably happened
very early in animal evolution, more than 600
million years ago. Most scientists agree that
circuits of interconnected neurons probably arose
soon thereafter, first as diffuse webs and later as a
centralized brain and nerves.
G. Miller, Science, 2009

115. s g
s nes akin ce
ciou se M tien
Co n Sen Sen
Communities
Bodies
Cells
Biomolecules
Atoms
Subatomic Particles
Strings (or whatever)

116. s g
s nes akin ce
ciou se M tien
Co n Sen Sen
Communities
Bodies
Cells
Biomolecules
Only living
(biological) Atoms
systems
??? Subatomic Particles
Strings (or whatever)

117. s g
s nes akin ce
ciou se M tien
Co n Sen Sen
Communities
Bodies
Cells
Biomolecules
? Atoms
Subatomic Particles
Strings (or whatever)

118. Biomolecules!!!

119. Only biomolecules???

120. Atoms!!!

121. Only atoms???

122. Subatomic particles!!!
10-18m
Strings
10-35m (or
whatever)

123. Conclusion:
While one may argue that sense making
and therefore some form of conciousness is
limited, extending downward in scale only
to the smallest, autopoietic elements of life
– namely the cell – a complexity analysis of
the universe (as a unified, self-organizing
and emergent system) reveals that the
universe is sentient throughout; that
sentience is inherent and universal in the
structures of existence.

124. Conclusion:
While one may argue that sense making
and therefore some form of conciousness is
limited, extending downward in scale only
to the smallest, autopoietic elements of life
– namely the cell – a complexity analysis of
the universe (as a unified, self-organizing
and emergent system) reveals that the
universe is sentient throughout; that
sentience is inherent and universal in the
structures of existence.

125. Conclusion:
While one may argue that sense making
and therefore some form of conciousness is
limited, extending downward in scale only
to the smallest, autopoietic elements of life
– namely the cell – a complexity analysis of
the universe (as a unified, self-organizing
and emergent system) reveals that the
universe is sentient throughout; that
sentience is inherent and universal in the
structures of existence.

126. Conclusion:
While one may argue that sense making
and therefore some form of conciousness is
limited, extending downward in scale only
to the smallest, autopoietic elements of life
– namely the cell – a complexity analysis of
the universe (as a unified, self-organizing
and emergent system) reveals that the
universe is sentient throughout; that
sentience is inherent and universal in the
structures of existence.

127. s g
s nes akin ce
ciou se M tien
Co n Sen Sen
Communities
Bodies
Cells
Biomolecules
? ? Atoms
Subatomic Particles
Strings (or whatever)

129. Single cell multiorgan plasticity
Diane Krause MD PhD
Saul Sharkis MD PhD, Michael Collector
Octavian Henegariu MD
Sonya Hwang MD, Rebekah Gardner
Sarah Neutzel

130. Cell Team
Jane Prophet
Mark D’Inverno
Rob Saunders
Peter Ride
Neil Theise
Discussions were part of the production of "Cell",
a collaboration across art and science
funded by a Wellcome Trust SciArt Award
and an award from Future Physical.
"Cell" is coordinated by Peter Ride
and is a DA2 Digital Arts Agency production.