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