Implications of the universe as a self-organizing system. Bodies are comprised of cells, Cells are comprised of molecules. Molecules are comprised of atoms. Atoms are comprised of subatomic particles. Subatomic particles arise from the smallest possible entities (e.g. strings?), and these arise from the energy rich vacuum in a quantum foam. "Everything only looks like a thing"

1. Icahn School of Medicine at
Mount Sinai
Neil Theise, MD
Department of Pathology
New York University School of Medicine
New York City
Stem Cells, Complexity
and the Science of Being

2. “Thinking is better than knowing,
but looking is even better.”
Goethe, “Maxims”

3. Goethe, “Maxims”
“Thinking is better than knowing,
but looking is even better.”

4.  Surprises in stem cell biology
 Complexity and Emergence
 Everything only looks like a thing!
 What/who are we…?

5.  Surprises in stem cell biology
 Complexity and Emergence
 Everything only looks like a thing!
 What/who are we…?

8. LethalLethal
IrradiationIrradiation
Male bone marrow transplantMale bone marrow transplant
F.I.S.H.F.I.S.H. forfor
Y-ChromosomeY-Chromosome

10. The Standard Paradigm:
Restricted Cell Plasticity

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

12. BEWARE
OF
DOGMA

13. The
Great
Stem Cell
Debate
2001

14. Embryonic Stem Cells
All three layers of the embryo:
Mesoderm,
Endoderm,
Ectoderm

15. Embryonic Stem Cells
All three layers of the embryo:
Mesoderm: muscle, blood, bone
Endoderm: visceral organs
Ectoderm: brain, nerves, skin
so….

16. Embryonic Stem Cells
Can make everything!

17. Embryonic Stem Cells
Can make everything, in order to:
perform cell transplants…
create artificial organs (livers!)
implant genes for gene therapies…

18. Embryonic Stem Cells
Can make everything!
Adult Stem Cells
Can make . . . ?

19. Sort PKH-brightSort PKH-bright
Male Donor BMMale Donor BM
Lin DepleteLin Deplete
ElutriateElutriate
PKH26PKH26
LabelLabel
48 Hours48 Hours
TransplantTransplant singlesingle cell intocell into
22oo
Female RecipientFemale Recipient
11oo
Female RecipientFemale Recipient

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

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

30. Irreversible gene restrictions

31. What if gene restrictions
are REVERSIBLE?

34. Controversy!!!

35. trivial...trivial...
vs.vs.
ROBUST!!!ROBUST!!!

36.  Surprises in stem cell biology
 Complexity and Emergence
 Everything only looks like a thing!
 What/who are we…?

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

38. Date: 9th May 2002
Location: Neil's office, New York
Jane says: “Ideas about pathways are interesting. AJane says: “Ideas about pathways are interesting. A
lot of people who are involved in digital biology arelot of people who are involved in digital biology are
interested in things like swarming people and sointerested in things like swarming people and so
called ’soup organism’ behaviour. And one of thecalled ’soup organism’ behaviour. And one of the
useful models to take forward is about antuseful models to take forward is about ant
colonies…”colonies…”

39. Complex Adaptive Systems:
Interacting individuals that,
if they fulfill 4 criteria,
organize themselves from the bottom up,
into larger structures…
ewin R, Complexity: Life at the Edge of Chaos. 2nd ed.
Chicago IL: University of Chicago Press; 2002.
ohnson S, Emergence. New York NY: Scribner; 2001.

40. Complex Adaptive Systems:

41. 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.

42. 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.

43. 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.

44. 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.ADAPTIVE.

45. Complex Adaptive Systems:
Rise and fall of economic markets
Urban development
Stem cells and tissue development and repair
Beatlemania
Rise and fall of civilizations
Evolution and speciation

46. Complex Adaptive Systems:
Rise and fall of economic markets
Urban development
Stem cells and tissue development and repair
Beatlemania
Rise and fall of civilizations
Evolution and speciation
Stem cells and formations of tissues, organs, bodies

47. Complex Adaptive Systems:
• Numbers matter

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

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

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

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

55. Low level engraftmentLow level engraftment
is not only NOT trivial,is not only NOT trivial,
but it is VITALbut it is VITAL
–– literally so.literally so.1-31-3
Low level engraftmentLow level engraftment
is not only NOT trivial,is not only NOT trivial,
but it is VITALbut it is VITAL
–– literally so.literally so.1-31-3
heise ND. Exp Hematology 2003heise ND. Exp Hematology 2003
Inverno M, Theise ND. BCMD 2004Inverno M, Theise ND. BCMD 2004
Inverno M, Theise ND, Prophet J.Inverno M, Theise ND, Prophet J.
In: Potten C, Wilson J, Clarke R, Renahan A:In: Potten C, Wilson J, Clarke R, Renahan A:
Tissue stem cells: Biology and applicationsTissue stem cells: Biology and applications

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

57. order
disorder
“chaos”

58. disorder
“chaos”
complex
adaptive
systems
order

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

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

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

62.  Surprises in stem cell biology
 Complexity and Emergence
 Everything only looks like a thing!
 What/who are we…?

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

68. ChRISTOPHER SWANN

69. Hierarchies of complex systems…
thing vs. phenomena
depends on scale of observation
=> COMPLEMENTARITY
Theise. Nature, May 2006
Theise & Kafatos, Complexity, 2013

71. Communities
Bodies
Cells

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

73.  Surprises in stem cell biology
 Controversies in stem cell biology!
 Complexity and Emergence
 Everything only looks like a thing!
 What/who are we…?

74. Communities
Bodies
Cells

75. Theise. Nature, May 2006
Theise & Kafatos, Complexity, 2013
Boundaries are relative...Boundaries are relative...
Implications of hierarchies of complex systems

76. Communities
Bodies
Cells
Biomolecules ?

77. Communities
Bodies
Cells
Biomolecules

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

79. 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

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

81. “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

82. “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

83. What kind of models?

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

89. 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

90. Still more implications of
complexity in life…

91. Communities
Bodies
Cells
Biomolecules
Atoms

92. Communities
Bodies
Cells
Biomolecules
Atoms

93. Communities
Bodies
Cells
Biomolecules
Atoms

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

95. Communities
Bodies
Cells
Biomolecules
Atoms
Subatomic Particles

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

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

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

100. . . . we are the universe

101. Diane Krause MD PhDDiane Krause MD PhD
Saul Sharkis MD PhD, Michael CollectorSaul Sharkis MD PhD, Michael Collector
Octavian Henegariu MDOctavian Henegariu MD
Sonya Hwang MD, Rebekah GardnerSonya Hwang MD, Rebekah Gardner
Sarah NeutzelSarah Neutzel
Single cell multiorgan plasticitySingle cell multiorgan plasticity

102. Cell Team
Jane ProphetJane Prophet
Mark D’InvernoMark D’Inverno
Rob SaundersRob Saunders
Peter RidePeter Ride
Neil TheiseNeil 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.

103. Bushell & Theise
“There’s no such thing as a central dogma
into which everything will fit...any mechanism
you can think of, you will find -- even if it is
the most bizarre kind of thinking.
“Anything...
“So if the material tells you, ‘It may be
this,’ allow that. Don’t turn it aside and call
it an exception, an aberration, a contaminant.
“So many good clues have been lost that
way.“
“A Feeling for the Organism”
Evelyn Fox Keller, 1983
Nobel-laureate Barbara McClintock: