Marcelle I. Cedars, M.D. Professor and Director

1. Preimplantation Genetic Diagnosis: Prevention of Disease vs. Selection of TraitsScience and Society Marcelle I. Cedars, M.D. Professor and Director Division of Reproductive Endocrinology and Infertility

3. Dependable birth control made sex without reproduction possible...Now medicine is closing the circle...by offering methods of reproduction without sex; including artificial insemination by donor (AID-TDI), in vitro fertilization (IVF), and surrogate embryo transfer (SET). As with birth control, artificial reproduction is defended as life affirming and loving by its proponents, and denounced as unnatural by its detractors. George Annas

4. Decisions regarding gametes and pre-embryos • Biological status of human pre-embryo • Human pre-embryo not a person • Human pre-embryo entitled to respect because it has the potential to become a person • Gamete donors have dispositional authority • Decisions should be made prior to formation of pre-embryos.

5. Area of Concern • Research vs. Clinical tool • When does ART require IRB approval? • Clinical tool • proven efficacy through formal evaluation • widely accepted as effective • widely utilized

6. Absence of Federal Funds for Research • Small improvements in pregnancy rates • Continued failure of 3rd party coverage • Continued use of high risk (multiples) techniques • Many important developmental steps arising outside the U.S. • Many developments arise in the private practice setting • Scientifically unproven techniques entering the clinical sphere

7. Research vs. Clinical Tool • Function of the IRB • protect the rights of the research subjects • review risks • understand the nature of the study • participation is voluntary

8. Clinical Tool • Someone has to be first • patient • physician • Issues of payment • Issues of consent

9. Clinical Tool • Unique areas of consent • emotionality of infertility • deals with the beginning of life • rapidly changing field

10. Preimplantation Genetic Diagnosis • Priority of disease prevention • Sex-selection for medical indications only • HLA matching • organ/stem cell donor • Correction of inborn errors

11. Embryo Development Day1 2 Pronuclei Day2 4-Cell Day3 8-Cell Day4Morula Day5 Blastocyst Day7 Blastocyst Hatching

12. PGD (Preimplantation Genetic Diagnosis) Blastomere Biopsy

13. Preimplantation Genetic Diagnosis • Is antenatal testing appropriate? • What do we, as physicians, do with the results? • What should patients be allowed to do with the results?

14. Preimplantation Genetic Diagnosis • Do we support genetic testing with chorionic villus sampling and amniocentesis? • Is this not just earlier testing, potentially avoiding late abortion? • How do you test techniques without embryo research? • For what do we test? • Where are the boundaries between the correction of genetic defects and the selection of genetic traits?

15. X-linked diseases Lesch-Nyhan Syndrome Duchenne muscular dystrophy X-linked mental retardation Adrenoleukodystrophy Hemophilia Fragile X Single-gene defects Sickle-cell anemia Cystic Fibrosis Tay Sach’s Disease Huntington’s Disease b-thalassemia Spinal muscular atrophy Myotonic dystrophy …… Diseases amenable to preimplantation genetic diagnosis

16. Diseases amenable to preimplantation genetic diagnosis • PGD offers couples at risk the chance to have an unaffected child without resorting to post-conception diagnosis and potential late gestation termination. • Patient preference (Musters, et al., 2009) • Many “at risk” couples (42%) were unaware of PGD • Once informed – most (74%) preferred PGD over PND

17. Diseases amenable to preimplantation genetic diagnosis • For diseases with known serious impact of morbidity or mortality – who pays? • Can only the rich afford this technology? • Should insurance companies pay for testing and diagnosis • Would this lower lifetime costs vs. the birth of an affected child • Should all patients have access – would not having access leave an increasingly small pool of affected children with less attention and resources? • Might this lead to coercion to test?

19. Reproductive Outcome • Lower pregnancy rate than with standard IVF/ICSI • Outcome strongly determined by age and number of oocytes • Genetic basis for PGD did not impact outcome • No increased risk to the health of a singleton birth Verpoest, et al., 2009 Liebaers, et al. 2009

21. PGD: Genetic variants associated risk • What increased risk warrants application of this technology? • Most are low-penetrance polymorphisms or low-risk alleles (RR 1.1-1.5) • And what risks do you substitute by the IVF process • ? Increased risks to the mother • ? Increased risk to child from prolonged culture for diagnosis

22. PGD: Genetic variants associated risk • How is the autonomy of the couple balanced against possible psychological risks to the child • What penetrance for cancer susceptibility genes warrants PGD • What about late onset diseases (e.g. Alzheimer’s) • In the U.S., with inequity in access to care, (especially ART) – would PGD further disadvantage low income members of society

23. PGD: Technical challenges • FISH • Hybridization failure • Signal overlap • PCR • Amplification failure • Contamination • Allele drop-out • CGH • Less efficiency with single cell • Better option for day 5 – trophectoderm biopsy • Time delay (72 hours) • Microarray • Oligonucleotide mutation probes

24. Washington Post

25. Pre-implantation genetic screening • Aneuploidy is the most common cause of pregnancy failure • This risk increases with maternal age • However, current evidence does not support use of PGS for women of advanced age, with recurrent IVF failure, recurrent pregnancy loss or to improve prognosis in good quality patients.

27. PGD: controversial issues • Positive selection • Selecting for the genetic trait: deafness, Achondroplasia • HLA matching • Tissue donation to an affected sibling • Gender selection for non-medical reasons • Selection for social traits: intelligence, athleticism….

28. Ethics and Public Policy • Respect for the human person • individual • society • Respect for the pluralism of our society • Avoid the “slippery slope” • actions • arguments

29. Parenthood • Hopes • Choices • ? Perfection • What happens to the child that isn’t “perfect”?

30. Human Genome Project • New choices • New responsibilities

31. Human Genome Project • All disease as a discrete entity • Huntington’s Disease • Illnesses have complex and subtle interactions • genes that predispose to sickle cell anemia - - “side effect” preventing malaria

32. Human Genome Project • Wise elimination of defects may present unforeseen consequences • “Genetic enhancement” • “playing God” • unexpected, unforeseen consequences

33. Human Genome Project • …..using the hopes and choices of parenthood as a guide, the Genome Project can be incorporated into the ethical framework of family dynamics and clinical medicine… Prof. Glenn McGee

34. Federally Funded Research • Rhythm of medical advances • discovery • speculation and dire predictions • time elapses - - no dire consequences • technique refined • technique becomes clinically useful Dr. Arthur Haney

35. Federally Funded Research • Critical research must be allowed • Science is intrinsically “good” • Should have appropriate public scrutiny • Technology can be either “good” or “bad” • Allow knowledge to overcome fear

36. The importance of dialogue • Reconciliation of views • individual • group • center staff • university or hospital • society • Importance of education