Gattaca- genetic screening was the basis of their society. Genetic elite called “Valids” while the inferior, naturally born children, called “invalids” or “faith births”!! Evokes much debate, Biological, bioethical and biblical From liberalism to doom. Stated in the bible Nebuchadnezzar dream of the end of days when “the iron mixed with clay mingle themselves with the seed of Man” There is a scence in Gattaca that is very similar to a scene everyday in IVF units. A couple in a doctors office, a monitor is showing their embryos chosen for embryo-transfer. “ this child is still you, simply the best of you! You could concieve a 100 times and never get such a result. Today, I hope to show you the current scientific data relating to the possibilities of designer babies
Vectors gene carriers genetic modifcation as we have seen in Transgenic animals and in GM plants Ex-vivo cells modified outside the body In vivo -direct gene transfer into the body Trials Most gene therapy targeted at cancer but now also interest in hereditary disease Designer baby not very likely Fears of iatrogenic effects Introduction of corrected gene in hemopoietic compartment or stem cell could cure some thalasaemias First attempts limited by the type of gene vectors used Needs High level of expression and newer approaches are with Lentiviral vectors (can infect non-dividing cell which is good for gene therapy) --------------------------------------------------------------- Robert Winston and cloning pioneer Ian Wilmut have already patented techniques for genetic modification Highly controvertial like to discrimiantaorty things and “enhancement” But can target only somatic cell gene therapy
1. Designer Babies in the Lab. Giles Palmer, Mitera IVF
2. BackgroundScience fiction Science todayWells, Huxley, Gattaca, Bladerunner, •IVF / embryo freezing/ PGDSplice, Judge Dredd, Halo, Star Wars, •Genome unraveled (1990-2003)Godsend, The Island, Aliens 4 etc. etc.. •First Artificial organism (Mycoplasma laboratorium) •First Synthetic life (Medusoid) •Dolly (1997) •Stem cell research •Nobel prize for cloning research- Gurdon & Yamanaka
3. What is a designer baby? • Designer baby- “journalistic phrase” • 2004 O.E.D “ a baby whose genetic make-up has been artificially selected by genetic engineering combined with in vitro fertilisation to ensure the presence or absence of particular genes or characteristics”
4. Reproductive choice• Philosophical & ethical debate• Parents want best for child-good parenting?• What reproductive freedom do we have? -Sex selection & family balancing-”Slippery Slope” leading to Neo-Eugenics -J. Med. Ethics 2002 reported a case where Deaf single women choose Deaf sperm donor• Religion/ Beliefs Greek Orthodox Church-”every human life has a beginning but no end… …..church ought to maintain reservations”.
5. The case for PGD• Clinical Application since 1989• Range of genetic disorders• PGS-screening for chromosomal abnormalities.• Increase pregnancy rate?• Embryo biopsy safe (Goossens 2008, Liebaers 2010)• Evolved as genetics has developed• Introduction of powerful genomic amplifying techniques- a-CGH, SNP arrays and karyomapping
6. PGD so far…• 10 yrs. of Data by ESHRE- • Limitations-technical, 27000 cycles mosaicism, timeframe • Normal embryos-only 42%• 61% for aneuploidy (Munne 2007) screening • Oocyte quality, Age of• 17% single gene disorders Patient,• 16% chromosomal disorders • Selection often limited in PGS/PGD cycles• 4% X-linked disease • Limited to the genes the• 2% social sexing parents already have!
7. IQ• Not for multiple genes, complex interactions
8. Eye colour 3 genes, still not fully understood: bey 1 (Chr 15) spectrum/pigment bey 2 (Chr 15) Brown-Blue gey 1 (Chr 19) Green-Blue
9. Designing babies• Healthy Children• How the parent raises child is designing• Human nature seeks and desires things that are rare.• If you want a particular trait…..
10. Designing babies• Healthy Children• How the parent raises child is designing• Human nature seeks and desires things that are rare.• If you want a particular trait…..use time honored method of choosing a partner who has the desired characteristics!
11. The case for saviour siblings / Bébé Medicament • Immunogenic typing for bone marrow transplantation • If no HLA identical available PGD can be used to select embryos HLA identical (or free of disease) • ESHRE SIG : Interest of sick child balanced with the interests of futuresuggested for neoplastic or congenital donor child.. if parents intend todiseases effecting the hematopoietic or love child it is non inherentlyimmune system disrespectful (Hum. Reprod., 2002, Pennings)
12. 1 r 200 gne - Wa itu tion onst c rec poieti m ato ful he ccessSu
13. The case for saviour siblings / Bébé Medicament •Min time is 12-18 months •High number of embryos needed •Age of mother, ovarian reserve •Success rate of HSC transplantation • •HFEA Not to be used for parent! •UNESCO considers PGD with theKant “dignity means that people must only goal HLA typing unethicalalways been treated as an end in •No organ transplantationthemselves and never only as ameans”
14. Mitochondrial Transplantation
15. Mitochondrial Transplantation • Oocyte transfer from fertile patients- 30 births (Cohen 2001) • First case of human modification (mtDNA heteroplasmy) • “Boost” embryo development
16. Mitochondrial Transplantation • Mitochondrial disease (1/4000 USA) • Mitochondrial Research Group (Turnbull, University of Newcastle) • Public debate HFEA
17. “Three-parent baby” • Review health and risks • Debate about if donor is genetic parent Donor contributes 0,1% of DNA (37 genes) • Ethically neutral??? • To be continued!!!!
18. Gene ModificationTransgenics Pharming: Isolate target protein from milk
19. Gene ModificationGene therapyuse of Vectors to introduce corrected gene•Target the right cells•Integrate Active the gene•Avoid side effects
20. Gene ModificationRisks•Marshall(1999) Ornithinetranscarbamylase deficiency:Adenovirus trial -Death•Hacien Bey (2003) SCID: Reportedcorrected cell function with functionalcytokine receptors•Transfusion of cells resulted in fullrestoration of immune function•Serious leukemia like disorder 30months after therapy
21. Gene ModificationGene therapy•Murine retroviruses (28%)- first to be used, small load, good targeting•Adenovirus- larger load, not for clinical studies (safety issues)•HSV, Pox virus- not widely used•Non Viral: Naked DNA injection, DNA Lipid complex•Lentivirus -promisingCavazzana-Calvo (Nature 2010) 33 months after lentiviral Β-globin gene transfer Adultwith severe Β(E)/B(O) thalassemia “dependent on monthly transfusions since childhoodhas become transfusion independent for last 21 months”•Artificial chromosomes-YAC, BAC, MAC and HAC
22. Gene ModificationArtificial chromosomes
23. Gene ModificationGene therapy•Murine retroviruses (28%)- first to be used, small load, good targeting•Adenovirus- larger load, not for clinical studies (safety issues)•HSV, Pox virus- not widely used•Non Viral: Naked DNA injection, DNA Lipid complex•Lentivirus -promisingCavazzana-Calvo (Nature 2010) 33 months after lentiviral Β-globin gene transfer Adultwith severe Β(E)/B(O) thalassemia “dependent on monthly transfusions since childhoodhas become transfusion independent for last 21 months”•Artificial chromosomes-YAC, BAC, MAC and HAC•Spermatozoa ( ICSI or injection into testis)- Winston, Wilmut
24. Germ line Modifications• IBC: Germ line interventions could be contrary to human dignity, rejects idea of testing/enhancing any human characteristic other than to alleviate suffering• Council of Europe 1997 a.13: ”an intervention seeking to modify the human genome may only be undertaken for preventative, diagnostic or therapeutic purposes and only if its aim is not to introduce any modification in the genome of any descendants”
25. The case for cloningPros Cons•Clone of deceased child •Loss of human dignity•Duplicate individual of Great •Unjustified power over clonegenius, beauty, physical ability •Welfare of the clone •Health issues •No reason to! •Inefficient •Identical?
26. The case for cloning
27. Health issues •• Pregnancy • Mortality Late puberty• Spontaneous abortions • Decreased Lifespan• Abnormalities-placental, low cotyledon • Rapid aging count, thickening fetal membrane, Hydrallantois, Edema of placental • Cloning skips gametogenesis membranes, hypertrophy of cotyledons, Edema of umbilicus • Reprogramming/imprinting/telomeres• Retarded development, abnormal growth curve, abnormal expression of mRNA• Post natal-• large birth size, in adequate organ development, lung dysmaturity, respiratory distress, metabolic acidosis Shoemaker 2006, Bertolini 2004, Lee 2004, Kato 2002, Xu 2000, Okonuki 2002 • Inefficient THCR (1-4%)
28. Use of Stem cells
29. Use of Stem cells
30. Stem cells• Therapeutic cloning use the cloning • Reproductive cloning procedure to produce procedure to produce a clonal embryo clonal embryo transferred to the uterus with to generate stem cells the intent to recreate a living organism
31. Generation of Chimeric Rhesus Monkeys • Totipotent cells in early embryos are progenitors ofCell, January 2012 all stem cells and are capable of developing into a whole organism, including extra embryonic tissues such as placenta. Pluripotent cells in the inner cell mass (ICM) are the descendants of totipotent cells and can differentiate into any cell type of a body except extra embryonic tissues. • The ability to contribute to chimeric animals upon reintroduction into host embryos is the key feature of murine totipotent and pluripotent cells. Here, we demonstrate that rhesus monkey embryonic stem cells (ESCs) and isolated ICMs fail to incorporate into host embryos and develop into chimeras. However, chimeric offspring were produced following aggregation of totipotent cells of the four- cell embryos. These results provide insights into the species-specific nature of primate embryos and suggest that a chimera assay using pluripotent cells may not be feasible.
32. The Clone Laws• Inspired by WHO, WMA, Helsinki Declaration on Biomedical Research, CIOMS• Convention of Human Rights and Biomedicine (1996)- Ban on Genetic research performed on humans, creation of h-Embryos for research• Council of Europe (1997) a.13: ”an intervention seeking to modify the human genome may only be undertaken for preventative, diagnostic or therapeutic purposes and only if its aim is not to introduce any modification in the genome of any descendants” Forbids “any intervention seeking to create a human being genetically ….identical to another human being, whether living or dead”• UNESCO-Universal declaration on Human Genome and Human Rights (1997)- Germ line modification - contrary to human dignity• UN General Assembly (2001) Committee against Reproductive cloning (UN cloning treaty 2003)• ESHRE-Extended moratorium of human cloning
33. Hybrids and Chimeras *
34. Mitochondrial Transplantation II • Review HFEA • Ooplasmic Transfer (OT) • Abnormalities ( Jacob 2006, Brown 2006) • Needs 50% to be effective so… • Nuclear Transfer (NT) into enucleated oocyte • 1.Nucleus of Unfertilized oocyte (De Wert 2000) • 2.Pronuclear transfer (Brown 2006,Turnbull 2010) • 3.Blastomere nuclear transfer (De Wert 2000) • Safety issues- mtDNA influence? • Ethical issues-is it Germline intervention??? Prohibed by Council of Europe 1997
35. Mitochondrial Transplantation II enucleated oocytes ET • NT type 1 • NT type 2 ET ET • NT type 3 If also ET isn’t this reproductive cloning ????
36. Mitochondrial Transplantation II • In grating a license for research to Newcastle University shown mtDNA ≠ nDNA NOT GERMLINE • Strong consensus that mtDNA does not alter or influence character ? • ? Cognitive capacity in mice (Thorburn 2001), • ? Facilitate Athleticism • Debate continues
37. Moral status of the embryo Hippocratic prescription “ἀ σκέειν, περὶ τὰ νουσήματα, δύο, ὠ φελέειν, ἢ μὴ βλάπτειν”Research, treatment and diagnosis effecting the genome should be undertaken only after rigorous prior assessment of potential risks and benefits Care to protect the vulnerable infertile couple to allow optimum chance of becoming parents with respect to all stages of the embryo Genetic screening for Medical indication  …..rest needs more debate