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  • Transcript

    • 1.
      • Summer 2007 Workshop
      • in Biology and Multimedia
      • for High School Teachers
    • 2. Stem Cell Research Overview Mountainous Path
    • 3. Outline
      • What are Stem Cells?
      • Potential Uses
      • Claims Against Using Stem Cells
      • Cultivation Process
      • Stem Cells and Cloning
      • Stem Cell Theory of Cancer
      • Worldwide Status
    • 4. What are stem cells?
      • Stem cells are undifferentiated cells that have many potential scientific uses:
        • Cell based therapies
          • Often referred to as regenerative or reparative medicine
        • Therapeutic cloning
        • Gene therapy
        • Cancer research
        • Basic research
    • 5. Two types of stem cells
      • Embryonic Stem Cells (ESC): received from:
        • Embryos created in vitro fertilization
        • Aborted embryos
      • Adult Stem Cells (ASC): can be received from:
        • Limited tissues (bone marrow, muscle, brain)
          • Discrete populations of adult stem cells generate replacements for cells that are lost through normal wear and tear, injury or disease
        • Placental cord
        • Baby teeth
    • 6. Source of ESC
      • Blastocyst
        • “ ball of cells”
        • 3-5 day old embryo
        • Stem cells give rise to multiple specialized cell types that make up the heart, lung, skin, and other tissues
      • Human ESC were only studied since 1998
        • It took scientists 20 years to learn how to grow human ESC following studies with mouse ESC
    • 7. How are embryonic stem cells harvested?
      • Human ES cells are derived from 4-5 day old blastocyst
      • Blastocyst structures include:
        • Trophoblast : outer layer of cells that surrounds the blastocyst & forms the placenta
        • Blastocoel : (“blastoseel”) the hollow cavity inside the blastocyst that will form body cavity
        • Inner cell mass : a group of approx. 30 cells at one end of the blastocoel:
          • Forms 3 germ layers that form all embryonic tissues (endoderm, mesoderm, ectoderm)
    • 8. Blastocyst http://www. ivf /infertility/infertility5. php
    • 9. Unique characteristics of Stem Cells
      • Stem cells can regenerate
        • Unlimited self renewal through cell division
      • Stem cells can specialize
        • Under certain physiologic or experimental conditions
        • Stem cells then become cells with special functions such as:
          • Beating cells of the heart muscle
          • Insulin-producing cells of the pancreas
    • 10. Unspecialization
      • Stem Cells are unspecialized
        • They do not have any tissue-specific structures that allow for specialized function
        • Stem cells cannot work with its neighbors to pump blood through the body (like heart muscle cells)
        • They cannot carry molecules of oxygen through the bloodstream (like RBCs)
        • They cannot fire electrochemical signals to other cells that allow the body to move or speak (like nerve cells)
    • 11. Self - Renewal (Regeneration)
      • Stem cells are capable of dividing & renewing themselves for long periods
        • This is unlike muscle, blood or nerve cells – which do not normally replicate themselves
        • In the lab, a starting population of SCs that proliferate for many months yields millions of cells that continue to be unspecialized
          • These cells are capable of long-term self-renewal
    • 12. Specialization of Stem Cells: Differentiation
      • Differentiation : unspecialized stem cells give rise to specialized (differentiated) cells in response to external and internal chemical signals
        • Internal signals : turn on specific genes causing differential gene expression
        • External signals include:
          • Chemicals secreted by other cells such as growth factors, cytokines, etc.
          • Physical contact with neighboring cells
    • 13. Differentiation
      • Why do your body cells look different although they all carry the same DNA, which was derived from one fertilized egg?
      • Differentiation example (
    • 14. Potential of Stem Cells (vocab)
      • Totipotent (total):
        • Total potential to differentiate into any adult cell type
        • Total potential to form specialized tissue needed for embryonic development
      • Pluripotent (plural):
        • Potential to form most or all 210 differentiated adult cell types
      • Multipotent (multiple):
        • Limited potential
        • Forms only multiple adult cell types
          • Oligodendrocytes
          • Neurons
    • 15. Adult Stem Cells
      • Adult or somatic stem cells have unknown origin in mature tissues
        • Unlike embryonic stem cells, which are defined by their origin (inner cell mass of the blastocyst)
    • 16. Reprinted with permission of Do No Harm.
    • 17. Adult stem cells continued
      • Adult stem cells typically generate the cell types of the tissue in which they reside
        • Stem cells that reside in bone marrow give rise to RBC, WBC and platelets
        • Recent experiments have raised the possibility that stem cells from one tissue can give rise to other cell types
          • This is known as PLASTICITY
    • 18. Adult Stem Cell Plasticity Examples
      • Blood cells becoming neurons
      • Liver cells stimulated to produce insulin
      • Hematopoietic (blood cell producing) stem cells that become heart cells
      • CONCLUSION: Exploring the use of adult stem cells for cell-based therapies has become a very important (and rapidly increasing) area of investigation by research scientists!
    • 19. Adult stem cells: A brief history
      • Adult stem cell research began about 40 years ago
      • Stem cell discoveries in 1960s:
        • Bone marrow contains 2 populations of stem cells
          • Hematopoietic stem cells – forms all blood cell types
          • Bone marrow stromal cells – mixed cell population that generates bone, cartilage, fat and fibrous connective tissue
        • Rat brain contains two regions of dividing cells, which become nerve cells
    • 20. History Cont.
      • Stem Cell Discoveries in the 1990s
        • Neural stem cells in brain are able to generate the brain’s three major cell types
          • Astrocytes
          • Oligodendroglial cells
          • Neurons
    • 21. Adult Stem Cell Facts
      • Adult stem cells were found in many more tissues than expected
      • Some may be able to differentiate into a number of different cell types, given the right conditions
      • General consensus among scientist:
        • Adult stem cells DO NOT have as much potential as embryonic stem cells
      • CLARIFICATION : not all new adult cells arise from stem cells
        • Most arise by MITOSIS of differentiated cells
    • 22. Potential Uses of Stem Cells
      • Basic research – clarification of complex events that occur during human development & understanding molecular basis of cancer
        • Molecular mechanisms for gene control
        • Role of signals in gene expression & differentiation of the stem cell
        • Stem cell theory of cancer
    • 23. Potential uses cont.
      • Biotechnology (drug discovery & development) – stem cells can provide specific cell types to test new drugs
        • Safety testing of new drugs on differentiated cell lines
        • Screening of potential drugs
          • Cancer cell lines are already being used to screen potential anti-tumor drugs
          • Availability of pluripotent stem cells would allow drug testing in a wider range of cell types & to reduce animal testing
    • 24. Potential uses cont.
      • Cell based therapies :
        • Regenerative therapy to treat Parkinson’s, Alzheimer’s, ALS, spinal cord injury, stroke, severe burns, heart disease, diabetes, osteoarthritis, and rheumatoid arthritis
        • Stem cells in gene therapy
          • Stem cells as vehicles after they have been genetically manipulated
        • Stem cells in therapeutic cloning
        • Stem cells in cancer
    • 25. Embryonic vs Adult Stem Cells
      • Totipotent
        • Differentiation into ANY cell type
      • Known Source
      • Large numbers can be harvested from embryos
      • May cause immune rejection
        • Rejection of ES cells by recipient has not been shown yet
      • Multi or pluripotent
        • Differentiation into some cell types, limited outcomes
      • Unknown source
      • Limited numbers, more difficult to isolate
      • Less likely to cause immune rejection, since the patient’s own cells can be used
    • 26. Claims against ESC (unsubstantiated thus far!)
      • Difficult to establish and maintain *
      • Difficulty in obtaining pure cultures from dish*
      • Potential for tumor formation and tissue* destruction
      • Questions regarding functional differentiation
      • Immune rejection
      • Genome instability
      • Few & modest results in animals, no clinical treatments
      • Ethically contentious
      * = same problem with ASC
    • 27. Cell Culture Techniques for ESC
      • Isolate & transfer of inner cell mass into plastic culture dish that contains culture medium
      • Cells divide and spread over the dish
      • Inner surface of culture dish is typically coated with mouse embryonic skin cells that have been treated so they will not divide
    • 28.
      • This coating is called a FEEDER LAYER
        • Feeder cells provide ES cells with a sticky surface for attachment
        • Feeder cells release nutrients
      • Recent discovery: methods for growing embryonic stem cells without mouse feeder cells
        • Significance – eliminate infection by viruses or other mouse molecules
      • ES cells are removed gently and plated into several different culture plates before crowding occurs
    • 29. Images depict stem cell research at the University of Wisconsin Madison.
    • 30. Cloning of whole organisms
      • Purpose:
        • Reproductive cloning in animals
        • Therapeutic cloning in animals
        • Breeding animals or plants with favorable traits
        • Producing TRANSGENIC animals that:
          • Make a therapeutic product (vaccine, human protein etc)
          • Act as animal models for human disease
          • Deliver organs that will not be rejected (cells lacking cell surface markers that cause immune rejection)
        • Vaccines in biotech industry: steps in cloning a gene
    • 31. SCNT: Somatic Cell Nuclear Transfer
      • SCNT is a method used for:
        • Reproductive cloning such as cloning an embryo
        • Regenerative cloning to produce “customized” stem cells & overcome immune rejection
      • Blastula stage cannot continue to develop in vitro
        • It must be implanted into surrogate mom
        • Surrogate mom is just a container that provides protection & chemical signals necessary for development
    • 32. http://www. kumc . edu / stemcell /early.html Reprinted with permission from the University of Kansas Medical Center.
    • 33. Reprinted with permission of Do No Harm.
    • 34. Challenges of Reproductive Cloning
      • Many animals were cloned after Dolly
        • Cats, pigs, mice, goats, cattle, rabbits
      • Obstacles:
        • Very inefficient process
        • Most clones have deleterious effects & die early
        • Surviving clones show premature aging signs
        • Signs of abnormal embryonic development:
          • Clones & their placentas grow much faster than expected in surrogate mom
    • 35. Therapeutic Cloning
      • 3 goals of therapeutic cloning by SCNT in humans:
        • Use embryo as source for ES cells
        • Use ES cells to generate an organ
          • In this case the organ generated will carry cells with the same genetic markers as the patient (recipient)
        • Correct genetic error in ESC in blastula stage
    • 36. Pitfalls of therapeutic cloning (1) Some immune rejection may occur- WHY?
        • About 1% of the DNA in the clone will NOT be identical to donor cell (patient)
        • It will be identical to egg cell used in SCNT
        • REASON: mitochonrial DNA in eggs
          • Human mitochondria carry about 13 genes, some of which code for surface proteins
    • 37. Pitfalls of therapeutic cloning (2)
      • Large number of eggs needed for SCNT
      • To harvest large number of eggs:
        • Excessive hormone treatment of females to induce high rate of ovulation
        • Surgery to retrieve eggs
          • Both can be harmful to female human
          • Cow/pig females may be used
        • Cow/pig eggs will carry species-specific mitochondrial genes
          • Mixing species is reason for concern!
    • 38. Common Opinions
      • Reproductive cloning is a criminal offense (it is ILLEGAL worldwide!)
      • Therapeutic cloning is acceptable, however there is still significant controversy over whether:
        • the clone is implanted into the uterus of surrogate mom? OR
        • the clone is explanted into culture dish to generate ES cells
    • 39. Stem Cell Theory of Cancer
      • 1855: Rudolf Virchow developed the Embryonal- Rest Hypothesis
        • Microscopic examination of tumor samples revealed many morphological (structural & functional) resemblances to ESC in a developing fetus
      • Isolation of teratoma: nonmalignant tumors
        • Teratoma represents a ball of almost all cell types
        • This indicates that teratoma may originate from unregulated stem cells that can give rise to almost all tissues
    • 40. Teratoma
      • Ovarian Teratoma
        • You can see teeth! tf /040802. htm Image courtesy of Leonard J. Tyminski, M.D., Radiologist at
    • 41. Current Efforts with SC and Cancer
      • Determine difference between cancer & normal stem cells
      • Identify potential points in pathways critical for the survival of cancer SCs
      • Develop therapies that specifically target cancer SC
      • Duke University Explanation
      Drawn by Christine Rodriguez Tumor stem cell Tumor cell
    • 42. Status of SC research in other countries
      • Great Britain
        • Very liberal policies on research
        • Therapeutic cloning allowed, use of excess embryos & creation of embryos allowed
        • Stem cell research allowed
      • France
        • Less liberal politics
        • Use of excess embryos from IVF allowed
        • Reproductive AND therapeutic cloning banned
      • Germany
        • Very strict policies
        • Use of excess embryos and creation of embryos banned
        • Scientists can IMPORT embryos
    • 43. Debate in US
      • Federal funding available for research using the Bush lines only:
        • ES cell lines that were already in existence by 8/9/01
      • Disadvantage of Bush stem cell lines:
        • May have lost regenerative ability
        • May have accumulated mutations or infections
      • Private companies continue to pursue stem cell research
        • Use of human embryos for IVF & therapeutic cloning is legal in most states
          • No federal funding
        • Some states are considering banning both
    • 44. Global Status
      • Ongoing debate regarding use of embryos
      • United Nations: proposal for a global policy to ban reproductive cloning only
    • 45. References
      • Stem cells & Cloning Stem cells & Cloning; David A. Prentice, Benjamin Cummings, 2003
      • Stem cells in class; Badran, Shahira; Bunker Hill Community College, 2007, Boston Museum of Science Biotechnology Symposium
      • Harvard Stem Cell Institute