Muscle, Marrow, etc'

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EMBRYONIC Stem Cells
SOMATIC (ADULT) Stem Cells
CNS
Muscle, Marrow, etc.
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Neural Cell Lineage
Brain (fetal, newborn, adult)
EGF bFGF LIF myc
Stem Cell

Progenitor Cell
Neuroblast
Glioblast
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Association Neuron
Projection Neuron
Oligo
Astrocytes
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Tracking NSCs to Tumors
Stem cell
Tumor
Day 9
Day 15
Day 22
Day 36
Weissleder et al Center for Molecular Imaging
Research, Harvard
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Aboody et al, PNAS, 2000
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Yandava et al, PNAS (1999)
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Park et al, Nature Biotech (2002)
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Host
NSC
NSC
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Teng, Y.D., Lavik, E.B., Qu, X., Ourednik, J.,
Zurakowski, D., Langer, R., Snyder, E.Y. (2002)
PNAS, 99, 3024-3029.
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Other Examples(NSC-mediatedrescue/
protection / regeneration -- complementing
cell replacement)Neural stem cells display an

• ALS (Lou Gehrigs Disease) / (?SMA)
• Parkinsons Disease
• Aging
• Cerebellar Degeneration
• Spinal Cord Injury
• Stroke
• Head Trauma

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Host
NSC
NSC
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How do we really best exploit stem cell biology?
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Which Are the Best Cells to Use?
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Low-Hanging Fruit

• Aspects of diseases where rescue of cells
  pre-existing circuits decrease in
  inflammation/scarring may be key
• (Cell Replacement Promotion of Host
  Regeneration a Bonus Protection of Established
  Circuits May be as Important More Tractable!
  than Establishing New Ones)
• ?Subacute Stroke/Spinal Cord Injury/head trauma
• (before muscle atrophy, contractures, scarring
  present insurmountable barriers)
• ?ALS / Parkinsons Dz -- for cell protection

• Pediatric Diseases (e.g., Stroke SCI TBI
  Neurogenetic Dzs)
• (harness developmental processes genes
  identified model for adult)

• Brain Tumors (differentiation unimportant
  simply benign tracker)

• Gene delivery vehicles (differentiation
  unimportant simply benign pump)

In Meantime, Prove Safety, Efficacy, Establish
Protocols, Learn, Observe
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How does one functionin the face of imperfect
and/or incomplete knowledge?
When that function is to Relieve Suffering
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HOW A PHYSICIAN MIGHT WEIGH SOME ASPECTS OF THE
ETHICAL DEBATE

• Equivalent to organ donation

• Sin to have the resources to help someone
  not use them

• Much of perplexity pivots on question
• When does human life begin?

• Brain death analogy

• Reasoning backwards from end of life to figure
  out the beginning of life
• We know when human life ends by loss of certain
  brain functions therefore, life cannot begin
  until those functions ensue

• Embryo -- not sentient no nervous system
  therefore, no personhood

• Fertilized egg Reproduction System/Tract
  necessary for even potential for person embryos
  in vitro not enabled (Guenin)

• ES cells not yet individualized -- twins
  could still form are seeds

• The inner cell mass is to a human being what
  lumber nails is a house in of itself
  does not have a plan (Caplan)

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QUANDARIES

• Use of Adult Tissues?

• May not be the same as embryonic/fetal cells
• different genetic propensities timing of
  programs
• Still need to be compared studied rigorously
  head-to-head with more immature/primordial
  cells
• For some organ systems, may be adequate because
  consistent with their biology
• e.g, for hematopoietic blood-based diseases or
  when hematopoietic blood cells are
  sufficiently therapeutic
• e.g., rescue effects alone
• For other organs system (e.g, non-regenerative
  organs or well cell replacement alone is
  therapeutic) may not be sufficient
• e.g., pancreas, nervous system

• Endogenous cells?

• Uncertain how to generate/direct sufficient
  numbers of site-specific, appropriate cell types
  in a practical, timely, efficient manner with
  minimal undesireable effects

• May not be well-suited for diseases with genetic
  basis already flawed

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QUANDARIES

• Present ES cell lines

• Not representative of diversity of America (from
  IVF clinics)
• Limited racial/ethnic backgrounds, HLA types
• May already bear disease gene -- hence, errant
  information
• Lack of genetic diversity in available lines
  thwarts attempts to study role of genetic
  variation in disease susceptibility correlate
  variable phenotypes with biochemical markers in
  culture
• Allelic variability is important -- 10-15 lines
  too few to study this

• May propagate misinformation -- compromise
  scientific integrity
• Weve generated hypotheses re human development
  disease based on present lines now need to
  test them against other control lines with
  standard criteria across multiple labs (markers)
• Therefore, may not be able to draw valid
  scientific conclusions

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QUANDARIES

• Present ES cell lines

• Under stringent IP restrictions
• Cant combine readily with another companys IP
  (biomaterials, genes, drugs)
• Restricted availability
• Very expensive to start the research
• 5000/line -- for few colonies that may or may
  not grow (especially with limited expertise)
• Need gt10-15 lines to study allelic variablilty
  -- costs prohibitive
• Subpopulations, subclones, variants of lines
  restricted
• Mutations, chromosomal inactivation issues
  require subclones
• Shared across labs -- no single lab can perform
  all experiments
• Each subclone or byproduct a new product
  covered under patent
• Cant share manipulated cells with collaborators
  to compare data, conserve resources, maximize
  expertise
• A lab with 1 skill shouldnt also have to be
  skilled in ESC growth
• Current rules restrict distribution of
  subclones, reporter lines, interesting variants
• Because of ownership issues, little venture
  capital for development of hESCs
• Public accountability not readily accessible if
  work done in private sector
• Your disease may not be a money-maker--
  i.e., low commerical priority

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QUANDARIES

• Present ES cell lines

• Expertise
• hESCs difficult to maintain in undifferentiated
  state, there is insufficient training for new
  investigators
• disparate labs doing same experiments, but no
  centralized database for sharing information
• from viewpoint of venture capital
• Technology some of preclinical risk for ESCs
  needs to be addressed by academia before
  companies can be started to commercialize
  products
• Academia has avoided ESC research because of
  funding uncertainty controversy
• Private sector does not have depth of academic
  biological firepower

• New lines could be used to create Models of
  Disease
• -- without nuclear transfer

• Americans will seek help elsewhere -- with risk
  of bad outcomes
• from inexperienced /or unscrupulous, venal
  practitioners

• Excess blastocysts pre-blastocysts are already
  discarded routinely freezing promotes
  degradation
• -- with no benefit to patients

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Arguments for Stem Cell Research to be Done In
Public -- Not Solely Private -- Sector

• Public Scrutiny -- Guard Against
• Ethical lapses (safeguard safety dignity of
  human subjects)
• Financial lapses

• Limits costs
• Therapies developed with public funds will be
  priced more reasonably
• Analagous to concern over price of prescription
  drugs in USA vs. country where government-sponso
  red health care (e.g., Canada)

• Enhanced Patient Safety Benefits
• Good data made public immediately
• Bad data not hidden
• Analagous to situation where side-effects from
  some anti-depressants not revealed
• Look beyond bottom-line
• Your disease of interest may not be a money
  maker, a priority
• Best research done in public sector -- in
  academia -- because have the arcane labs
  resources needed for understanding
• Membrane biophysicists, electrophysiologists,
  signal transduction biologists, etc.
• Scientists working with yeast, drosophila,
  zebrafish

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Southern California Stem Cell Consortium

• Development,
• plasticity,
• aging,
• regeneration
• Multi-organ
• Multi-species
• Multi-models

• Science --
• collaborations
• pool data/techiques
• training grants
• program projects
• Education Training
• Bioethics Public Policy

2nd Thurs. Morning of Every Month 930am-1100am F
ishman Auditorium Burnham Institute, La Jolla
esnyder_at_burnham.org
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THREE PILLARS

• SCIENCE
• Pool data, techniques, collaborations
• Better techniques for isolation/translation
• How characterize stem cells
• Better understanding of disease processes
• Distribute reagents, knowledge (including
  database)

• EDUCATION
• Training -- high school, professionals, industry
• Outreach -- policy makers, public
• Internships - scientists, teachers, journalists,
  officials,
• ethicists

• PUBLIC POLICY BIOETHICS
• Panel
• Symposia

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Leveraged Investment
California Institute for Regenerative Medicine
CIRM Funds
Disease Groups
Foundations
Private Industry
Research Institutions
Total Funds Available for Research
Increased State Revenues
Decreased State Healthcare Costs
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Broad Participation InGovernance Oversight

• Decisions On Recommendations
• Scientific Medical Grant Funding for
  Meritorious Research
• In public sector under public scrutiny
• With benefits (including royalties) to the public
  sector
• Scientific Medical Research Standards
  Regulations
• Rigorous Financial Ethical Oversight
• Facilities To House /or Promote Meritorious
  Research

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Designed For Win-Win

• For researchers
• Establish long-term funding stream for
  pluripotent stem cell somatic stem/progenitor
  cell research
• 300 Million/ year -- 3 Billion over 10 years
• Additional 300 Million for new facilities
• Insulate this funding stream from political
  volatility
• Predictable funding future
• Insulate research discoveries from limited
  ownership of IP
• Open research areas not currently supported by
  Federal government
• Fund a critical mass of scientific inquiry
• Concurrent scientific medical inquiry across
  broad range of diseases
• Create synergistic opportunities across
  disciplines
• Multi-disciplinary, Multi-organ Multi-species
• Do stem cells share common sets of principles?
• Foster collaboration sharing dissemination of
  insights data
• Attract retain the best researchers to the
  field
• Attract, train, retain students, post-docs,
  young faculty
• Attract retain capital investment

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Designed For Win-Win

• For the State its Citizens
• Generate new jobs tax revenues
• Attract investments companies
• Provide a positive impact on State budget during
  economic recovery
• Insures broader public dissemination of findings
  new insights
• And if we can do the fundamental academic
  biology
• Reduce suffering of patients families (within
  outside of California)
• Reduce healthcare cost burden on patients by
  developing new therapies
• Potential reduction in state health care program
  costs
• Reducing costs by just 1 would save 1 Billion
  annually pay for itself within a few years
  amortize the Initiatives 3B over 30 years
• Any advance -- a molecule, a drug, an antibody s
• Analogy to polio vaccine, anti-TB drugs,
  antibiotics, anti- psychotic drugs
  anti-depressants

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???
PERSON WITH SPORADIC OR HEREDITARY DISEASE
PERSON WITH SPORADIC OR HEREDITARY DISEASE
Nuclear Transfer NT (from a somatic cell)
ADAPTED BY LARRY GOLDSTEIN EVAN SNYDER FROM
WWW.NIH.GOV/NEWS/STEMCELL/FIG4B.GIF
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???
PERSON WITH SPORADIC OR HEREDITARY DISEASE
PERSON WITH SPORADIC OR HEREDITARY DISEASE
Nuclear Transfer NT (from a somatic cell)
ADAPTED BY LARRY GOLDSTEIN EVAN SNYDER FROM
WWW.NIH.GOV/NEWS/STEMCELL/FIG4B.GIF
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???
PERSON WITH SPORADIC OR HEREDITARY DISEASE
immunohistocompatible
Nuclear Transfer NT (from a somatic cell)
ADAPTED BY LARRY GOLDSTEIN EVAN SNYDER FROM
WWW.NIH.GOV/NEWS/STEMCELL/FIG4B.GIF
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Ultimately, we believe we can use the biology
itself to reason through issues, to determine
common ground, to find roads to
consensus. Good ethics start with good facts.
CNS
Muscle, Marrow, etc.