Jim Wells, Ph.D Assistant Professor Division of Developmental Biology Children’s Hospital

1. Stem cell potential Jim Wells, Ph.D Assistant Professor Division of Developmental Biology Children’s Hospital Research Foundation of Cincinnati James.wells@cchmc.org 513-636-8767

2. Google search for “human stem cell ethics” 1 Google “Hits” (x 1,000,000) 2700% increase 0.5 2002 2004 August 2005 2003

3. (~10% type 1)

4. Stem cells Pluripotent embryonic stem cells PSCs Adult stem cells Also cord blood stem cells

5. Goal of all stem cell research stem cell PSC/ES cells in vitro Adult stem cells Make Therapeutic Cells in vitro (in a petri dish) Therapeutic cell Cure disease

6. Source of pluripotent/embryonic stem cells ~20 cells 0.1mm 4/1000th inch Human embryo 4 days after in vitro fertilization Eye of a needle

7. Making pluripotent Stem Cell lines Donated surplus eggs from IVF clinics Cell Line Cells will grow Indefinitely in a petri dish Make billions of copies Limitless supply of Potential therapeutic cells Other options * Keep Frozen Discard as medical waste * It is esimated that 400,000 surplus eggs are stored/frozen in the US

8. Pluripotent Stem Cell lines Cell line 1 Wisconsin Cell line 2 Göteborg Cell line 3 Haifa

9. Examples of what PSCs can become (Crohne’s disease) (Alzheimer’s Multiple Sclerosis) Gut cells (Oteoporosis) Brain neurons Bone cells Spinal cord neurons (Muscular Dystrophy) Muscle cells (Paralysis) Potential limitless supply of any diseased cell Skin cells Heart cells (Burns) (Cardiovascular disease) Blood cells b-cells (Diabetes) (Anemia, Cancer)

10. Examples of Adult stem cells Skin stem cells ? Blood stem cells X No adult stem cell for b-cells in vivo ~50,000,000,000,000 total cells Muscle stem cells

11. Comparison of stem cells • First isolated in November, 1998 • Pluripotent - can become all cell • types of the body • Can multiply indefinitely in vitro • Un-tested therapeutically Human PSC’s • First identified 4 decades ago • Multipotent - can become some • cell types of the body • Limited replication in vitro • Some therapeutics available Human adult SC’s

12. Future stem cell therapeutics Human PSC’s ? • Diabetes • Alzheimer’s • Stroke • Cardiovascular disease • Autoimmune disease • Parkinson’s • Cancer • Burns • Spinal chord injury • Birth defects ? Human adult SC’s

13. Future stem cell therapeutics • Alzheimer’s • Cardiovascular disease • Cancer • Burns • Spinal chord injury ? Human adult SC’s

14. Future stem cell therapeutics Human PSC’s ? • Diabetes • Stroke • Autoimmune disease • Parkinson’s • Birth defects

15. Future stem cell potential We don’t yet know which type of stem cell will ultimately cure these different diseases

16. Approved pluripotent Stem Cell lines Cell line 1 Wisconsin Cell line 2 Göteborg Cell line 3 Haifa There are between 11 and 20 approved lines available at the stem cell registry at the National Institutes of Health. Developed before August 2001

17. Current stem cell lines have limited therapeutic potential because: Significant differences exist between cell lines Grown with mouse cells as “feeders” Little genetic diversity Corporate funding/proprietary issues Excludes use of patient-specific cell lines

18. Significant differences between cell lines • Physically different • Genetically different/chromosomal abnormalities • Multiply differently • Differences in their ability to become therapeutic cell types?

19. Are these differences important? Different lines may have different therapeutic potential, or none at all ? Wisconsin b-cells ? NOTHING Göteborg ? Haifa nerves Hundreds of different cell types in the body affected by disease

20. Human PSCs grown with mouse cells Feeder mouse cells provide important nutrients to help PSCs grow ALL existing cell lines were originally grown with mouse cells Possibility that mouse pathogens/viruses contaminate all cell lines Scientists have recently learned how to grow PSCs on human cells New “mouse free” cell lines have become available but are unapproved Human PSC Mouse viruses? Mouse feeder cell

21. Little genetic diversity with existing cell lines Transplanted cells are rejected when they come from a genetically different donor Closely matched genetic background increases the probability of a successful transplantation More cell lines from diverse genetic groups are needed "No matter how we look at it, the federally approved cell lines are inadequate, we can do a lot of work with them, but we can't move into clinical trials or offer therapies with them.” J. Gearhart, Johns Hopkins Medical Institute, Panel discussing the clinical use of PSC/ES cells.

22. Pitfalls of relying corporate development Proprietary issues Reduced scientific collaboration slows progress Less ethical oversight - full disclosure in academia "the absence of federal funding would mean a reduced role for federal oversight of the ethics of human embryonic stem cell research.” Ruth Faden, Ph.D., M.P.H. Executive Director of the Phoebe R. Berman Bioethics Institute at Johns Hopkins. Panel discussing the clinical use of PSC/ES cells.

23. 5. Patient specific stem cells: Somatic cell nuclear transfer/Therapeutic cloning Donated surplus eggs from IVF clinics Grow replacement cells in vitro Derive Patient-specific cell line Transplant cells therapeutic cloning No rejection of transplanted material Somatic cell Nuclear transfer

24. Somatic cell nuclear transfer Reproductive cloning Donated surplus eggs from IVF clinics Transfer to uterus reproductive cloning Somatic cell Nuclear transfer

25. Somatic cell nuclear transfer Reproductive cloning X Donated surplus eggs from IVF clinics X Transfer to uterus reproductive cloning All scientists I’ve spoken with think reproductive cloning is immoral and should be illegal. Somatic cell Nuclear transfer