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Stem Cells: Hype and Promise


... irradiated mice resulted in colonies of mixed blood cells ... original tumor. Different clonogenic cells within. the tumor give rise to phenotypically ... – PowerPoint PPT presentation

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Title: Stem Cells: Hype and Promise

Stem Cells Hype and Promise
  • What they are, how they are used and can they
    ever provide clinical benefits?

Todays Agenda
  • Historical perspectives
  • Hematopoietic (blood forming) stem cells
  • Embryonic (totipotent) stem (ES) cells
  • Cancer stem cells
  • Possible futures

  • Pluripotent stem cells cells capable of limited
    differentiation potential, i.e. blood forming
  • Totipotent stem cells cells capable of giving
    rise to an entire animal, i.e. embryonic stem
  • Cancer stem cells mutated pluripotent(?) stem
    cells that give rise to tumors
  • Cloning The derivation of an exact piece of DNA,
    cell or entire organism from a pre-existing entity

Early Clues in the pre-cellular world (18th
  • Regeneration in hydra-cut the organism (a simple
    invertebrate) in two and get 2 new organisms
  • Regeneration in echinoderms-cut off a starfish (a
    complex invertebrate) leg and watch as a new one
  • Regeneration in amphibians-cut off an amphibian
    (a vertebrate) leg or tail and watch a new one
  • The conclusion is that there is something (cells)
    in the adult capable of forming new and complex

20th century cell biology mouse teratomas
  • Teratomas are germ cell (sperm/oocyte) tumors
    that give rise to a variety of tissues including
    teeth and hair!
  • The stem cells of the teratoma are cancerous,
    while the differentiated cells are not
  • Transplantation of cancerous teratoma stem
    cells into normal embryos gives rise to
    completely normal adults.
  • These results suggested that stem cells could be
    studied and used to give rise to entire animals
  • These results were also the first to suggest that
    animals could be cloned.

Immature Teratoma
Hematopoietic (blood-forming) stem cells-the
pluripotent cell
  • Early microscopy data suggested that skin and gut
    cells turn over rapidly and, therefore, they
    must be replenished
  • Even more striking was the turnover of blood
    cells, particularly white blood cells
  • Billions of these cells must be replaced daily,
    and the source of these new cells was clearly the
    bone marrow
  • The effects of radiation on the bone marrow of
    A-bomb victims led scientists to show that X-rays
    were lethal mainly because of their effects on
    blood cell formation
  • This led to an explosion of data in murine
    systems on the nature of the blood-forming stem

Mice are very good for some things, like studying
blood stem cells
  • Anemic mice could be rescued by transplantation
    of embryonic blood cells
  • Transplantation of bone marrow cells into
    gamma-irradiated mice resulted in colonies of
    mixed blood cells growing in spleens-the first
    evidence for a blood stem cell
  • The hematopoietic stem cell is extremely rare
  • 25 years and countless irradiated mice were
    required to isolate a cell that, when injected
    into a lethally irradiated animal, could
    replenish the bone marrow and mature blood
  • This cell is the pluripotent hematopoietic stem
  • Bone marrow transplants are now routine clinical

Deterministic model of hematopoiesis
Tissue culture changes everything-the totipotent
  • Tissue culture is the ability to grow cells in
    plastic dishes using nutrient medium
  • This allows for the isolation of large numbers of
    cells for further study
  • While teratoma stem cells could be grown in
    culture, there was a nagging suspicion that they
    were abnormal
  • Therefore, a search was done to isolate normal
    counterparts of these tumor stem cells from
  • This resulted in the isolation and growth in
    culture of embryonic stem (ES) cells, derived
    from the inner cell mass of the embryo

Derivation of murine ES cells
  • Inner cell mass (ICM) gives rise to the embryo
  • ICM is microsurgically removed
  • ICM is placed in tissue culture with feeder
    cells and grows
  • A single ES cell from the ICM can make an entire
  • It is, therefore, toptipotent

An entire mouse can be made from a single ES cell
  • ES cells can be grown in culture permanently
  • The cell is plucked out of culture and injected
    into the ICM of a different strain of mice
  • The injected blastocysts is transplanted into an
    adult uterus
  • Offspring derived from the transplanted cell have
    different colored coats
  • They are genetically identical clones of the ES
  • The same thing can be done with any species,
    including us

Microsurgery on an egg
Mutant mice can be made from genetically
manipulated ES cells
Cancer stem cells
  • Previous work suggested that teratomas contained
    a tumor stem cell
  • Blood tumors (leukemias) also were found to
    contain a stem cell
  • A search was undertaken in solid tumors (brain
    and breast) for a stem cell that gave rise to the

Breast cancer stem cells give rise to different
cell types
Stochastic model
Cancer stem cell model
Cancer stem cells give rise to phenotypically
diverse cells that recapitulate the complexity of
the original tumor.
Different clonogenic cells within the tumor give
rise to phenotypically similar cells in new
Isolation of cancer stem cells
Flow Cytometry
Tumor formation by human breast cancer cells
B38.1CD44 CD24- injection
B38.1CD44 CD24 injection
Therapeutic Implications of Cancer Stem Cells
Therapy against an oncogenic mutation that is
expressed by cancer stem cells
The tumor is eliminated
Therapy against an oncogenic mutation that is
not expressed by cancer stem cells
The tumor inititially shrinks- but
The self-renewing cancer stem cell regenerates
the tumor

Possible futures
  • Production of genetically desirable organisms
  • Production of new tissues in culture
  • Cloning of humans

Production of genetically desirable organisms
  • This has already been done with plants-so called
    GM crops-these modified stem cells (seeds) can
    be made resistant to a diversity of pathogens and
  • Using ES cells, any gene can be easily mutated or
  • The modified ES cells can subsequently be used to
    give rise to a whole animal containing the
    mutated/overexpressed gene
  • This will likely be useful in food production as
    well as animals producing pharmaceuticals

Rapid engineering of genetically desirable traits
into animals
Production of new tissues in culture
  • ES cells can be used to form a diversity of
    differentiated cells in different culture
    conditions culture
  • Blood, cardiac myocytes, neurons etc. have all
    been differentiated from totipotent ES cells
  • The problem is that there are insufficient
    numbers of these cells and, with the exception of
    blood, they are hard to integrate into existing
  • While highly hyped, this procedure is a long way
    from clinical applicability

Tissue replacement with culture-differentiated
stem cells
Why would anyone want to be cloned?
  • Some people are psychotic
  • It would allow for possibly greatly enhanced
  • Because the clone would be genetically identical,
    organs and blood could be transplanted as we age
  • This would take care of many of the diseases that
    kill us
  • There are obviously ethical problems with this,
    for example, the clone, which is another human,
    would need to be dispatched to get the matched
    tissues (except for some cases, like blood, one
    kidney, etc.)

Could any of us be cloned?
  • Amazingly, yes (with caveats)
  • Early frog experiments showed that a nucleus from
    a completely differentiated cell could give rise
    to an entire frog
  • Decades later, the same experiment was repeated
    in mammals (dolly)
  • Most animals born this way have many
    physiological problems

Nuclear Cloning
The bottom line on mammalian cloning
Further Reading (Amazon)
  • The Proteus Effect Stem cells and Their Promise
    for Medicine, Ann Parsons
  • Human Embryonic Stem Cells an Introduction to
    the Science and Therapeutic Potential, Ann
    Kiessling and Scott Anderson
  • Stem Cells Scientific Progress and Future
    Research Directions National Institutes of Health

Enjoyment Reading
  • Einstein 1905 the Standard of Greatness, John
  • Incompleteness the Proof and Paradox of Kurt
    Goedel, Rebecca Goldstein
  • The Great Mortality an Intimate History of the
    Black Death, the Most Devastating Plague of All
    Time, John Kelly