Stem Cells: Scientific Potential and Alternatives

1. Stem Cells: Scientific Potential and Alternatives Glenn Sauer, Ph.D. Biology Department Fairfield University

2. Scientific Principles • What are stem cells? • How are they used? • What is the potential for therapeutic applications? • More information: • www.nih.gov

3. Review of Terminology • DNA - deoxyribonucleic acid, makes up genes • Gene - functional unit of heredity, a segment of DNA located at a specific site on a chromosome; genes direct the formation of proteins. • Nucleus - a membrane bound structure in the cell which contains the chromosomes. • Cell - the basic unit of life, all living organisms are made up of cells • somatic cell - a cell of the body (220 types in humans) • germ cell - an egg or sperm

4. Differentiation of Human Tissues • Early embryonic cells unspecialized • Three primary tissue layers: • Ectoderm • Mesoderm • Endoderm • All tissues develop from here

5. Adult Stem Cells Stem cells = cells that havethe ability to divide for indefinite periods and give rise to specialized cells Progenitor cells = partially specialized cells that can give rise to particular cell types

6. Stem Cells of the Bone Marrow

7. The Problem of Cell Potency • Unipotent - cell divides to produce same cell type; most cells • Multipotent- can give rise to some cell types; adult stem cells • Pluripotent- able to give rise to most cell types; embryonic, very small number of adult stem cells • Totipotent - unlimited cabability; can give rise to all cell types; only in early embryos

8. Early Embryological Development

9. Derivation of Human Pluripotent Stem Cells • John Gearhart (1998) - embryonic germ (EG) cells cultured from gonadal ridge of 5- to 9-week old fetal tissue obtained from elective abortions. Proc. Natl. Acad. Sci. USA 95: 13726-13731. • James Thomson (1998) - embryonic stem (ES) cells derived from inner cell mass of blastocysts created through in vitro fertilization procedures and donated for research purposes. Science 282: 1145-1147.

10. Derivation of hESCells • “Excess” frozen blastocysts donated from fertility clinics • Inner cell mass (embryo) separated from trophoblast (placenta) • Cells dissociated and cultured in laboratory • Can be made to differentiate using chemical signals

11. Applications of Pluripotent Stem Cells • Basic research in human development • “decision-making genes” (birth defects, cancer) • Drug development • human cell lines for all cell types • Cell therapies • replacement tissue for degenerative conditions (Parkinson’s and Alzheimer’s disease, diabetes, heart disease, stroke, arthritis)

12. Example: Diabetes • Insufficient insulin production in pancreas • Insulin needed for glucose uptake • “Islet-like” cells derived from stem cells produce insulin • Eliminates need for insulin injections

13. Scientific Challenges Remaining • Understanding of cellular events that lead to differentiation and specialization • Immunologic rejection - Can stem cells be modified to minimize tissue incompatibility? • Time of development and expense of treatments

14. Rejection: Possible Solutions • Genetic engineering • Somatic cell nuclear transfer (SCNT) • develops into a blastocyst • Dolly the sheep • cloning (banned by Congress)

15. The Controversy • Tremendous potential • scientific community • medical profession • patient advocates • Religious/ethical conflict • human dignity • abortion issue

16. When does “Human” Life Begin? • Genetic view - at conception (fertilization) • Embryologic view - after 14 days when each embryo can produce only one individual • Mental activity view - after 25 weeks when the human-specific EEG can be measured (death is defined as the loss of EEG) • Birthday view - life begins when infant is “metabolically” independent of mother

17. The Bush Decision - Aug 9, 2001 “We must proceed with great care” - limited approval for ongoing research. • Fully funded: adult stem cells, umbilical cord • Restricted: embryonic (existing cell lines only) • 64 existing lines • 20 in United States • Sweden, India, Australia, Israel • Unfunded: new donor embryos, cloned embryos Total federal funding for 2001: $ 250 M

18. Reaction to Bush Decision • Scientists • some $$ better than none • 64 cell lines not enough • concerns about control • Conservative Christians • relief that more research is not allowed • broken campaign promise • Patient Advocates • cautious optimism • emotional pleas for more $$

19. Religions Ponder the Issue • Roman Catholic, Evangelical Christians - opposed since stem cells are derived from the destruction of embryos • Most groups do not have official positions • Most common positions: • Judaism - supportive since it serves a common good (fighting disease) • Muslim - abortion is wrong but life begins when fertilized egg touches womb • Presbyterian, UCC - “generally supportive”

20. State Response • California voters approve Proposition 71 which provides $3 Billion for stem cell research (2004) • Other states approve similar measures (Connecticut, Florida, Illinois, Massachusetts, Missouri, New Hampshire, New York, Pennsylvania, Texas, Washington, Wisconsin)

21. Stem Cell Research Enhancement Act • Would allow use of surplus in vitro fertilization embryos with donor permission (2005) • Passed House of Representatives (238-194) and Senate (63-37) • Vetoed by George Bush (2006) • Stem Cell Therapeutic and Research Act of 2005 (enacted) • Provides funds for adult stem cell therapies and umbilical cord stem cells

22. Current Situation • Barack Obama executive order allows research with new stem cell lines (2009) • BUT Dickey Amendment to 1995 Appropriations Bill bans funds for human cloning or any research that voluntarily destroys embryos. • RESULT Research Labs using state funds to create stem cell lines and federal funds to work with the cells

23. Alternatives to hES Cells • Umbilical cord blood • Contains hematopoietic and mesenchymal stem cells (lower potency than hES) • Patient specific • Cord blood banks • $2000 collection and $125/year storage fees • Some public banks for donated cells

24. Alternatives to hES Cells • Induced Pluripotent Stem Cells (iPS)

25. Alternatives to hES Cells • Induced Pluripotent Stem Cells (iPS) • Uses Oct4, Sox2, Klf4 and c-Myc genes • Show higher potency than cord cells • Low efficiency (recent improvements) • Other problems • Abnormal aging • Tumor production • Incomplete reprogramming

26. Alternatives to hES Cells • Direct Cell Reprogramming - 2011 • Turns one cell directly into another • (ex. Skin cell  Neuron) • Uses mRNA, no viral vector • Eliminates need for stem cells • Potential and problems are uncertain

27. Autologous Stem Cell Therapies • Self-donation of mesenchymal stem cells • Injected (with or without chemical treatment) into injury site • Not FDA approved • Clinical trials underway (heart attack, spinal cord injury, etc.) • Many Americans seek overseas options • No proven effectiveness • Costly • High pressure sales tactics

28. Questions? • The United States has been criticized by some for being too restrictive to stem cell-based research and therapies. Should U.S. laws be relaxed to be more accommodating to those wishing treatment? • A recent study by Duke University predicted that by the year 2050, regenerative procedures based on stem cell and other biotechnologies could extend an average human life span by up to 100 years. Is this a desirable goal? • Many biotechnologies are vastly expensive, yet much of the basic research supporting these developments is paid for by taxpayers. Who should benefit?