Stem Cell Research

1. Stem Cell Research Jacques Mistrot M.D.

2. Can we vs. Should we? • Dramatic advances of modern molecular biology and genetics will continue at an accelerating pace • We must ask the morality questions before attempting the “can we” questions? We must not commit moral evil to produce moral good

3. “Humanity’s moral capacity has not kept pace with it’s technological skill . . . contemporary society is truly ill.” Joseph Cardinal Ratzinger, October 24, 2004.

4. Stem Cell/Cloning Topics • What are stem cells? • Possible uses of the technology • Current status/knowledge • Questions and known problems • Ethics, morality and Church teaching

5. Stem Cell – Definition • Self renewable: a cell that has the ability to continuously divide • Pluripotent: ability to develop into several different kinds of cells/tissues • Repair: ability to return function to damaged cells in the living organism

6. Kinds of Stem Cells Totipotent Pluripotent Multipotent

7. Day 2 2-cell embryo Day 3-4 Multi-cell embryo Day 1 Fertilized egg Day 5-6 Blastocyst Day 11-14 Tissue Differentiation Stages of Embryogenesis

8. Isolate inner cell mass (destroys embryo) Outer cells (forms placenta) Inner cells (forms fetus) Culture cells Day 5-6 Blastocyst Culture Medium Liver Heart repaired Kidney Heart muscle Derivation and Use of Embryonic Stem CellLines

9. Neural Retinal Bone Cartilage Epithelial ESC’s Differentiate Into Different Tissue Types (Tumors)

10. Possible Uses of Stem Cell Technology • Repair of defective cell types (Type 1 diabetes, Parkinson’s disease, heart disease, nerve damage) • Replace tissues/organs? • Study of embryology and diseases • Development of new drugs

11. Embryonic Stem Cells (ESCs) vs. Adult Stem Cells (ASCs)

12. Sources of ESCs • “Excess” embryos from In Vitro Fertilization • “Therapeutic” Cloning • “Induced” pluripotent stem cells - iPS

13. In Vitro Fertilization • Combination of sperm and eggs in the laboratory to produce a zygote (embryo) • Multiple embryos are produced • Embryos are grown in the laboratory until they reach the 6-10 cell stage (day 2-3) • Embryos are implanted (usually 3-4) in the mother’s uterus • “Excess” embryos are frozen for possible later use

14. Conceptualization of “Therapeutic Cloning”

15. Cloned Embryonic Stem Cells – Advantages/Problems • Advantages • Minimal rejection (patient’s own DNA) • Problems • Only 25% of clones became embryos • Only 5% of embryos survived to become a cell line • 1% success rate (animals) Embryodestroyed

16. Therapeutic vs. Reproductive Cloning • SCNT = Somatic Cell Nuclear Transfer • The technique of nuclear transfer to a de-nucleated egg cell is the same for either type of cloning • The difference is the destination of the newly formed human life (embryo) • Implantation(reproductive) vs. Destruction (therapeutic)

18. Therapeutic vs. Reproductive Cloning • Once “therapeutic” cloning is legalized – who will stop “implantation” ? • Genetic enhancement could be around the corner once reproductive cloning is legalized – athletes, geniuses = $$$

19. Claims for ESC’s UnsubstantiatedCurrent and potential problems for ESC’s • No current clinical treatments in humans -Geron Corporation • Few therapy successes in animal models • Difficulties in obtaining pure cultures in vitro • Questions regarding what tissues they will develop into • Problems of immune rejection (foreign DNA) • Potential for tumor formation and destruction of normal tissue into which they are implanted • Ethically contentious when source is destroyed IVF or cloned embryos

20. Early Successes – Adult Stem Cells • Human bone marrow stem cells (when exposed to various growth factors) turned on genes found in bone, cartilage, fat, muscle, blood, endothelial, nerve and liver cells. • Amnionicfluid stem cells recently shown to have similar traits to ESC’s with less chance of rejection. • Umbilical cord blood promises to replace bone marrow as a source of stem cells with less chance of rejection.

21. Adult Stem Cells Adult stem cells have been isolated from – amniotic fluid heart peripheral blood cartilage umbilical cord blood thymus placenta dental pulp brain tissue adipose tissue muscle cornea salivary gland pancreas tendon liver skin nasal mucosa

22. Ample Evidence that Adult Stem Cells show Pluripotent Capacity Adult stem cells from bone marrow can form new neurons in the human brain.Proceedings of the National Academy of Sciences USA 100, 1364-1369, 4 Feb 2003. Transplantation of adult bone marrow stem cells can repair patients’ hearts.The Lancet 361, 45-46, 4 Jan 2003. Adult stem cells from bone marrow can form all body tissues.Nature 418, 41-49, 4 July 2002. Patients receiving adult bone marrow stem cell transplant – stem cells also formed liver, skin, digestive tract.NEJM 346, 738-746, 7 March 2002. A single adult mouse bone marrow stem cell can form functional marrow, blood cells, liver, lung, gastrointestinal tract, skin, heart and skeletal muscle.Cell 105, 369-377, 4 May 2001. Adult stem cells from brain can grow into a wide variety of organs – heart, lung, intestine, kidney, liver, nervous system, muscle, and other tissues.Science 288, 1660-1663, 2 June 2000.

23. Current Clinical Uses of Adult Stem Cells • Cancers – Lymphoma, leukemias, breast, renal, ovarian, etc. • Autoimmune diseases – multiple sclerosis, systemic lupus, rheumatoid arthritis, etc. • Anemias– (incl. sickle cell anemia) • Immunodeficiencies – including human gene therapy • Bone/cartilage deformities – children with osteogenic imperfecta • Corneal scarring – generation of new corneas to restore sight • Repairing cardiac tissue after heart attack – bone marrow or muscle stem cells from patient • Parkinson’s – retinal, nasal or neural stem cells • Growth of new blood vessels – to prevent gangrene • Gastrointestinal lining – regenerate ulcerous tissue • Skin – grafts grown from hair follicle stem cells – burns, etc. • Wound healing– bone marrow stem cells stimulate skin healing • Spinal cord injury– clinical trials currently in Portugal, Italy, S. Korea

24. Current Uses of Stem Cells Adult Stem Cells:ESC: Retinoblastoma None Ovarian Cancer Merkel Cell Cancer Testicular Cancer Lymphoma Acute Lymphobolastic Leukemia Acute Myelogenous Leukemia Chronic Myelogenous Leukemia Juvenile Myelomonocytic Leukemia Angioimmunoblastic Lymphadenopathy with Dysproteinemia Multiple Myeloma Myelodysplasia Breast Cancer Neuroblastoma Non-Hodgkin's Lymphoma Hodgkin's Lymphoma Renal Cell Carcinoma Various Solid Tumors (Continued)

25. Current Uses of Stem Cells Adult Stem Cells:ESC: Soft Tissue Sarcoma None Scleromyxedema Multiple Sclerosis Crohn's Disease Rheumatoid Arthritis Juvenile Arthritis Systemic Lupus Polychondritis Systemic Vasculitis Sjogren's Syndrome Behcet's Disease Myasthenia Red Cell Aplasia Autoimmune Cytopenia X-Linked Lymphoproliferative Syndrome X-Linked Hyperimmunoglobuline-M Syndrome Severe Combined Immunodeficiency Syndrome-X1 Sickle Cell Anemia Sideroblastic Anemia (Contiued)

26. Current Uses of Stem Cells Adult Stem Cells:ESC: Waldenstrom's Macroglobulinemia None Aplastic Anemia Amegakaryocytic Thrombocytopenia Chronic Epstein-Barr Infection Fanconi's Anemia Diamond Blackfan Anemia Thalassemia Stroke Osteogenesis Imperfecta Sandhoff Disease Corneal Regeneration Hemophagocytic Lymphohistiocytosis Primary Amyloidosis Limb Gangrene Surface Wound Healing Heart Damage Parkinson's Disease Spinal Cord Injury (72 diseases successfully treated by adult stem cells thus far)

27. Adult Stem Cells Problems • Found in small numbers in most tissues except bone marrow, placenta, amnionic fluid and cord blood • Grow slowly in tissue culture • OCT4, NANOG genes (2005) • NASA micro-gravity growth technique (2005) • Growth factor cocktail – 10x increase (2006) • Amnionic fluid cells grow rapidly

28. Adult Stem Cells Advantages • Promising source of treatment • Able to generate virtually all adult tissues • Can multiply almost indefinitely, providing numbers sufficient for clinical treatments • Proven success in laboratory culture • Proven success in animal models of disease • Proven success in current clinical treatments • Ability to “home in” on damage • Avoid problems with tumor formation • Avoid problems with transplant rejection (same person donor or good tissue-match) Avoid ethical dilemma

29. Moral and Ethical Considerations of Stem Cell and Cloning Research • Adult stem cells • None • Cloned embryonic stem cells • Embryo destroyed • Reproductive cloning is a possible result • Embryonic stem cells from IVF • Embryo must be destroyed • Defense of embryo destruction is based on embryos ”not being persons” + utilitarian philosophy

30. Right to Life The Declaration of Independence of the United States guarantees “certain unalienable Rights, that among those are Life, Liberty and the pursuit of Happiness”

31. When Does Human Life Begin? Medical Embryology Textbooks The Developing Human: Clinically Oriented Embryology “Zygote: this cell results from the union of an oocyte and a sperm. A zygote is the beginning of a new human being (i.e., an embryo). Human development begins at fertilization… This highly specialized, totipotent cell marks the beginning of each of us as a unique individual.” Moore and Persaud:The Developing Human.

32. Personhood

34. Common Definitions of Personhood Functional - • Self-consciousness • Capacity to reason • Capacity to communicate Potentiality- Arguments For Using Embryos Utility - Size -

35. Embryo Is Not a Person – Personality definition problems • What traits define personhood? • Who makes the definition? • Society has excluded certain humans from personhood before (e.g., African slaves, Jews, etc.) Should we make a new list of human non-persons?

36. Personhood:Functional “Embryo Is Not a Person. . .” “Persons . . . are members of a social community that shapes and values them, and personhood must be defined in terms of interactions and relationships with others.” Susan Sherwin. 1999. Ethical Issues: Perspectives for Canadians. Ed. Soifer, Eldon. Peterborough, Ontario: Broadview Press, p. 267

37. Personhood:Functional • The lack of certain functional personality traits would remove from personhood: • Those who are in a coma • Elderly with degenerative disorders (Alzheimer's, etc.) • Most children under 3 years old • Mentally deficient Is is okay to consider these human beings as non-persons?

38. Personhood:Potentiality Claim: • Embryos are only potentiallife because most do not result in births in nature Science estimates: • Only 1/3 of natural embryos implant • Once implanted only 2/3 embryos survive to birth – ~80% lost

39. “Potential Life” • Nature takes life in many ways – aTsunami may take thousands of lives • Because life is lost through natural means is not the same thing as taking those lives by intent! • To destroy an embryo because it is only potential lifein nature is also not justified

40. Utility“Frozen embryos are going to be discarded anyway and should be used for research to help mankind” • Utility dictates the sacrifice of some for the benefit of others • Always arbitrary – usually strong vs weak • Nazi experimentation was utilitarian • Prisoners on death row are also going to die, so why not do research on them?

41. Size“Just a small ball of cells” • Does size defines humanness? • Is a teenager more human than an infant because of size? • Is a basketball player more human than a dwarf?

42. The Human Embryo • Biologically a human being • An integral being – a self-sustaining organism • Retains the same genetic identity through all subsequent stages of development -from embryo to death! • Once, we all looked just like this!

43. Catholic Church Teachings

44. Is the Catholic Church opposed to all stem cell research? The Church is not opposed to research involving adult stem cells, normally obtained from adult tissue, umbilical cord blood, placenta and other sources that pose no moral problem.

45. Why is the Church opposed to stem cell research using the embryo? • Because harvesting these stem cells kills the living human embryo. • The Church opposes the direct destruction of innocent human life for any purpose, including research.

46. Is the human embryo a person? • By “person” the Church means an individual human being endowed with a rational and immortal human soul. • Does the embryo have an immortal soul from the moment of conception?

47. Donum Vitae, I.1 “The conclusions of science regarding the human embryo provide a valuable indication for discerning a personal presence at the moment of this first appearance of human life: how could a human individual not be a human person?” CONGREGATION FOR THE DOCTRINE OF THE FAITH 

48. Reason tells us that by virtue of the fact that the embryo is a human being, it should be accorded all the respect of a human person. The Church teaches us that we should treat the embryo, from the moment of conception as if it were a human person.

49. Is the Church telling us to choose the lives of embryos over the lives of suffering patients? No. We are called to respect both, without discrimination . . . We must help those who are suffering, but we may not use an evil means to justify a good end.

50. Non Embryo-Destructive Methods To Produce Embryonic-Like Stem Cells