Clinical and ethical issues in reproductive technology - Viewpoint from embryologist

1. Clinical and ethical issues in reproductive technology -Viewpoint from embryologist scientist W.S.B. Yeung Department of Obstetrics and Gynaecology, University of Hong Kong

2. First test tube baby 18 July 1978

3. Ethical issues from IVF • IVF • Family structure, surrogacy • Cryopreservation • Posthumous baby • Preimplantation genetic diagnosis • Desinger baby • Selection of embryos for HLA

4. New reproductive technologies • Human embryonic stem cells • Somatic nuclear transfer • patient-specific embryonic stem cells • human-animals hybrid embryos

5. ART? Human embryonic stem cells Cell replacement therapy ES cells Thomson et al., 1998 Science. 282:1145-7

6. Human embryonic stem cells • Ethical issues: • Killing of embryos • Creation of embryos • Potential in regenerative medicine • Source of embryos • Supernumerary embryos (Hong Kong) • Creation of embryos (Mainland China, United Kingdom)

7. Creation of embryos NOT for infertility treatment • FIGO Committee for the Study of Ethical Aspects of Human Reproduction and Women’s Health • Allowed if data cannot be obtained using supernumerary embryos • Nuclear reprogramming by oocytes • Patient specific stem cells • Women should not be unduly induced for donating oocytes

8. Embryonic stem cells without immunorejection is required • Embryonic stem cell lines with different HLA  immunorejection • Embryonic stem cells for cell therapy • Production of stem cells with different HLA • Somatic nuclear transfer • Induced pluripotent stem cells

9. Dolly (February 1997) Somatic nuclear transfer Normal oocyte 277 nuclear transferred 29 implanted 1 live birth Somatic cell Enucleated oocyte Cloning

10. Cloning in reproductive medicine • Natural cloning more often after assisted reproduction (monozygotic twins) • Reproductive cloning is not allowed in most countries • Therapeutic cloning

11. Autologous graft  Gene therapy Diseased tissue Normal tissue ES cells Nucleus Normal oocyte Enucleated oocyte Therapeutic cloning No rejection

12. Patient-specific embryonic stem cells Evidence of a Pluripotent Human Embryonic Stem Cell Line Derived from a Cloned Blastocyst Science (2004), 303 1669 Fabricated data Both papers were retracted Patient-Specific Embryonic Stem Cells Derived from Human SCNT Blastocysts Science. (2005) 308:1777-83

13. Therapeutic cloning • Prohibitions in Hong Kong: • “to bring about the creation of a human embryo for the purpose of embryo research” • “to replace the nucleus of a cell of an embryo with a nucleus taken from any other cell” • “to clone any embryo”

14. Treatment of cytoplasmic defectby somatic nuclear transfer Defective embryo Nucleus Normal oocyte Enucleated oocyte

15. Somatic nuclear transfer • Low success rate, a high miscarriage rate, and complications. • Research should continue as a tool for studying • Nuclear-cytoplasmic interaction • Nuclear reprogramming • Genetic disorder

16. Human-animal hybrid embryos • Human oocytes are limited • Animal oocytes readily available • Interspecies embryos possible Cloning endangered gray wolves (Canis lupus) from somatic cells collected postmortem. Oh HJ et al. Theriogenology. 2008 Jun 3. [Epub ahead of print]

17. Embryonic stem cells generated by nuclear transfer of human somatic nuclei into rabbit oocytes Chen Y, He ZX, Liu A, et al Cell Research (2003) 13, 251–263. …The derived ntES cells are human based on karyotype, …. The ntES cells maintain the capability of sustained growth in an undifferentiated state, and form embryoid bodies, which, on further induction, give rise to cell types … that express markers representative of all three germ layers.

18. Human-animal hybrid embryos • No shortage of animal oocytes • Provide experimental model on studying nuclear reprogramming • Alternative source of patient-specific stem cells • Hong Kong: “combine human and non-human gametes or embryos or any part thereof such as to give rise to a two-cell zygote for research” is prohibited

19. Takahashi et al. (2007) Induced pluripotent stem cells • Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Takahashi K, Yamanaka S. (2006) Cell 126:663-76. • Repeated in human fibroblasts • Takahashi et al. (2007) Cell 131:861-72. • Yu et al. (2007) Science 318:1917-20. Science’s Breakthrough of 2007

20. Induced pluripotent stem cells • Transfection of 4 transcriptional factors  stem cell-like • Treatment of Sickle Cell Anemia Mouse Model with iPS Cells Generated from Autologous Skin Hanna J, Wernig M, Markoulaki S, Sun CW, Meissner A, Cassady JP, Beard C, Brambrink T, Wu LC, Townes TM, Jaenisch R (2007) Science 318: 1920-1923

21. Induced pluripotent stem cells  embryonic stem cells • global gene-expression patterns • DNA methylation (Oct3/4 and Nanog,H19 and Igf2r) • Tumor formation rate Researches on embryonic stem cells need to be continued

22. Summary • New reproductive techniques give rise to ethical issues. • Ethics vs Benefit • Prohibition vs Regulation

23. Thank you