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Who Are We?Who Are We?Stem Cells, Complexity and Stem Cells, Complexity and
the Science of Beingthe Science of Being
Neil Theise MDDepartments of Pathology & Medicine
Beth Israel Medical Center – Albert Einstein College of MedicineNew York City
www.neiltheise.com
““Thinking is better than knowing…Thinking is better than knowing…
Goethe – “Maxims”Goethe – “Maxims”
““Thinking is better than knowing,Thinking is better than knowing,
but LOOKING is even better!”but LOOKING is even better!”
Goethe – “Maxims”Goethe – “Maxims”
Haruna et al. Hepatology 1996; 23: 476
Aleta and James Crawford for Theise et al., Hepatology. 1999; 30: 1425.
Definitions according to:
Roskams, Theise et al., Hepatology 2004; 39: 1739-45.
The NormalLiver Lobule:
The NEW NormalLiver Lobule:
LethalLethalIrradiationIrradiation
Male Bone Marrow TransplantMale Bone Marrow Transplant
FISH forFISH forY-ChromosomeY-Chromosome
Theise & Krause, et al. Hepatology Jan 2000
Sort PKH-brightSort PKH-bright
Male Donor BMMale Donor BM
Lin DepleteLin DepleteElutriateElutriate
PKH26PKH26LabelLabel
48 Hours48 Hours
Transplant Transplant singlesingle cell into cell into 22oo Female Recipient Female Recipient
11oo Female Recipient Female Recipient
Bone Marrow
One Adult Cell
Epithelia of • Liver• Lung• Gut, (Pancreas)
Skin, Hair follicles
MESODERM
ENDODERM ECTODERM
One Adult Cell
One Adult Cell
True clonality = True adult stem cell plasticity!
The Standard Paradigm:The Standard Paradigm:Restricted PlasticityRestricted Plasticity
Irreversible gene restrictions
Embryology &Adult Tissue Reconstitution
Self renewal
What if gene restrictionsWhat if gene restrictionsare REVERSIBLE?are REVERSIBLE?
BEWARE OF
DOGMA
3 Principles of Plasticity3 Principles of Plasticity
Theise & Krause
BCMD, May 2001Leukemia, April Fool’s Day 2002
Comptes Rendus Biologies, December 2002
1.1. Genomic Completeness
2.2. Cellular Uncertainty
3.3. Stochasticity of Cell Origins and Fates
1. Genomic Completeness
2.2. Cellular UncertaintyCellular Uncertainty
3. Stochasticity of Cell Origins and Fates
“…the internal and the external co-determine the cell.”Richard Lewontin, 2000
2nd Principle:Cellular Uncertainty
Any attempt to observe a cell alters the state Any attempt to observe a cell alters the state of that cell at the time of characterization of that cell at the time of characterization
and and potentiallypotentially alters the likelihood of alters the likelihood of subsequent differentiation events.subsequent differentiation events.
2nd Principle:Cellular Uncertainty
Any attempt to observe a cell alters the state Any attempt to observe a cell alters the state of that cell at the time of characterization of that cell at the time of characterization
andand potentiallypotentially alters the likelihood of alters the likelihood of subsequent differentiation events.subsequent differentiation events.
??
Meanwhile, back at the plasticity debates…
Controversy!!!
trivial...trivial...vs.vs.
ROBUST!!!ROBUST!!!
Conversations with Jane ProphetNew Media Artist and
Professor, Interdisciplinary StudiesUniversity of Westminster, London UK
SciArt Award, Wellcome Trust 2002
Conversations with Jane ProphetNew Media Artist and
Professor, Interdisciplinary StudiesUniversity of Westminster, London UK
SciArt Award, Wellcome Trust 2002
Date: 9th May 2002 Location: Neil's office, New York
Jane says: “Ideas about pathways are interesting. A Jane says: “Ideas about pathways are interesting. A lot of people who are involved in digital biology are lot of people who are involved in digital biology are interested in things like swarming people and so interested in things like swarming people and so called ’soup organism’ behaviour. And one of the called ’soup organism’ behaviour. And one of the
useful models to take forward is about ant useful models to take forward is about ant colonies…”colonies…”
Complex Adaptive Systems:1,2
1Lewin 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.
…
Complex Adaptive Systems:Interacting individuals that,
if they fulfill 4 criteria,organize themselves from the bottom up,
into larger structures
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,
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!
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 ADAPTIVEADAPTIVEand are referred to as
emergent self-organizationemergent self-organization
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?
Complex Systems
Real world
Complex Systems
Real
Virtual
Complex Systems
Real
Virtual
Complex Adaptive Systems:Rise and fall of economic markets
Urban developmentBeatlemania
Rise and fall of civilizationsEvolution and speciation
Immunology
Complex Adaptive Systems:Rise and fall of economic markets
Urban developmentBeatlemania
Rise and fall of civilizationsEvolution and speciation
ImmunologyConciousness
Complex Adaptive Systems:
• Numbers matter
Complex Adaptive Systems:
• Numbers matter
• Negative feedback loops
Complex Adaptive Systems:
• Numbers matter
• Negative feedback loops
• Interactions are local without global sensing
Complex Adaptive Systems:
• Numbers matter
• Negative feedback loops
• Interactions are local without global sensing
• Low level randomness
Complex Adaptive Systems:
• Numbers matter
• Negative feedback loops
• Interactions are local without global sensing
• “Quenched disorder”
Low level engraftment Low level engraftment is not only NOT trivial, is not only NOT trivial, but it is VITAL but it is VITAL – – literally so.literally so.1-31-3
Low level engraftment Low level engraftment is not only NOT trivial, is not only NOT trivial, but it is VITAL but it is VITAL – – literally so.literally so.1-31-3
11Theise ND. Exp Hematology 2003Theise ND. Exp Hematology 200322D’Inverno M, Theise ND. BCMD 2004D’Inverno M, Theise ND. BCMD 200433D’Inverno M, Theise ND, Prophet J.D’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
Implications of Cell Lineagesas Complex Adaptive Systems
Mass extinctions.
order
disorder
“chaos”
disorder
“chaos”
complex adaptive
systemsorder
Implications of Cell Lineagesas Complex Adaptive Systems
Mass extinctions, eg:
? Aplastic anemia
? Fulminant liver failure
Implications of Cell Lineagesas Complex Adaptive Systems
The price of adaptation,
i.e. of LIFE,
is DEATH
Implications of Cell Lineagesas Complex Adaptive Systems
Hierarchies of complex systems…
Implications of Cell Lineagesas Complex Adaptive Systems
Hierarchies of complex systems…
thing vs. phenomena
depends on scale of observation
CommunitiesBodiesCells
e.g. cities, cultures, ecosystems, GaiaBodiesCells
CommunitiesBodiesCells
Biomolecules ?
CommunitiesBodiesCells
Biomolecules
ToshioYanagida
&Company
CommunitiesBodiesCells
Biomolecules
More implications, of course.More implications, of course.
1. Genomic Completeness
?? Cellular UncertaintyCellular Uncertainty
3. Stochasticity of Cell Origins and Fates
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 livingorganisms, but this concept breaks down at different perspectives and scales.”
CommunitiesBodiesCells
Biomolecules
“The validity of cell doctrine depends on the scale at which the body is observed…
CommunitiesBodiesCells
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…
CommunitiesBodiesCells
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
CommunitiesBodiesCells
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, postmodernera of biological investigation.”
CommunitiesBodiesCells
Biomolecules
What kind of models?
for example,2 models from Ancient Greece:
Is the body made of… indivisible subunitsindivisible subunits or an endlessly divisible fluidan endlessly divisible fluid
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
A study of acupuncture mechanism by magnetic resonance elastographyChan QC, Li G, Ehman RL, Rossman PJ, Cao G, Li R, Yang ESConf Proc IEEE Eng Med Biol Soc. 2004;2:1022-4.
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
CommunitiesBodiesCells
BiomoleculesAtoms
CommunitiesBodiesCells
BiomoleculesAtoms
We are walking, talking Earth…
CommunitiesBodiesCells
BiomoleculesAtoms
Subatomic Particles
Put group portrait from menla conference HERE
Beyond cell doctrine:Complexity thery informs alternate models of the bdy
For cross cultural dialogue
Neil D. Theise
www.neiltheise.com
Macroscopic body
Microscopic body
Nanoscopic body
Quantum body
Macroscopic body
Microscopic body
Nanoscopic body
Quantum body
e.g. physical therapysurgery
e.g. cell therapies
e.g. molecular medicineantibiotics
e.g. electromagnetics
Macroscopic body
Microscopic body
Nanoscopic body
Quantum body
e.g. yogatai chi
e.g. acupuncture?
e.g. traditional remedies
e.g. energy healing?meditation?
Macroscopic body
Microscopic body
Nanoscopic body
Quantum body
CoarseBody
?
EnergyBody
?
SubtleBody
?
Indo-Tibetan Medicine/Physiology
Macroscopic body
Microscopic body
Nanoscopic body
Quantum body
CoarseBody
?
EnergyBody
?
SubtleBody
?
Indo-Tibetan Medicine/Physiology
CommunitiesBodiesCells
BiomoleculesAtoms
Subatomic ParticlesStrings (or whatever)
CommunitiesBodiesCells
BiomoleculesAtoms
Subatomic ParticlesStrings (or whatever)
The Quantum Foam
We don’t live in the universe . . .
. . . we are the universe
The Relative
The Absolute
Implications of EverythingEverythingas Hierarchical Complex Systems
Buddhist Metaphysics
Implications of EverythingEverythingas Hierarchical Complex Systems
Jewish Mysticism
Implications of EverythingEverythingas Complex Adaptive Systems
Hindu Mysticism
Marrow-Liver PlasticityDiane KrauseJames CrawfordTavi HenegariuRomil SaxenaSunil Badve
Single Cell PlasticityDiane KrauseMichael CollectorSaul SharkisTavi Henegariu
Canals of HeringJames CrawfordRomil SaxenaBernard PortmannSwan Thung
Agent-based modelingof stem cell systems
Mark D’InvernoRob SaundersJane ProphetPeter Ride