Living is a risky endeavour - less so through genetic medicine?
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Das Wunder der Vererbung DiakoniePublik 3/2001 Blueprint of Life Cell Nucleus Chromosom Gene Gene-product: Protein DNA Informationsübertragung bei der zellteilung Cell division: Transfer of Information! DNA as carrier of Information H O C in phosphate ester chain Minor groove C and N in bases P Major groove Base pairs Sugar phosphate backbone 5‘ 3‘ Human ß-Globin, Segment TAAGCCAGTG TACGGCTGTC TGGAGCCACA CTCCCAGGAG GCTGGGCATA TATTGCTTAC TGTTCACTAG GGTGCACCTG CGTTACTGCC GGATGAAGTT GTTGGTATCA GGAGACCAAT CAGAGAAGAC CTGACTCTCT CCACCCTTAG GGACCCAGAG ATCTGTCCAC ACCCTAAGGT CCAGAAGAGC ATCACTTAGA CCCTAGGGTT CAGGGAGGGC AAAGTCAGGG ATTTGCTTCT CAACCTCAAA ACTCCTGAGG CTGTGGGGCA GGTGGTGAGG AGGTTACAAG AGAAACTGGG TCTTGGGTTT CTGCCTATTG GCTGCTGGTG GTTCTTTGAG TCCTGATGCT GAAGGCTCAT ... CAAGGACAGG CCTCACCCTG GGCCAATCTA AGGAGCCAGG CAGAGCCATC GACACAACTG CAGACACCAT AGAAGTCTGC AGGTGAACGT CCCTGGGCAG ACAGGTTTAA CATGTGGAGA CTGATAGGCA GTCTATTTTC GTCTACCCTT TCCTTTGGGG GTTATGGGCA GGCAAGAAAG ... Human ß-Globin, Exon1, Segment ...GTG CAC CTG ACT CCT GAG GAG Val His Leu Thr Pro Glu Glu AAG TCT GCC GTT ACT GCC CTG Lys Ser Ala Val Thr Ala Leu TGG GGC AAG GTG AAC GTG ... Trp Gly Lys Val Asn Val + 126 further AS TGA Stop !!! ! Genomic Library of Mankind • 46 Chromosomens 2 * 3,2 Milliarden Buchstaben • 30 000 – 40 000 Genes • ca. 99 % not protein-coding • Man/Chimpanzee 1-2% global text difference (ca. 120 Mio Letters) • enormous repetitive segements • Retroviral Traces (hundreds of thousands) Genomic Library of Individual Person • ca. 2 Mio Differences (SNPs) (between non-related persons) • ca. 60 000 of them in coding regions • ca. 10 000 genetic defects (each individual carries about 5) • every 500 -2000 letters a variation Evolutionary Traces in the Genome • 25 % of the human genome are „deserts" • ca. 50 % are repetitions • among them ca. 45 % „jumping copies", (silent since millions of years) • Museum of viral infections Genomic Non-sense but important identification tag! Person 1 : CA CA CA CA CA CA CA (Father ?) CA CA CA CA Person 2: (Father ?) CA CA CA CA CA CA CA CA CA CA CA CA CA CA CA CA CA CA Person 3: (Mother) CA CA CA CA CA CA CACA CA CA CA CA CA CA CA Person 4: (Father ?) CA CA CA CA CA CA CA CA CA CA CA CA CA CA CA CA CA Person 5: (Child) CA CA CA CA CA CA CA CA CA Die ersten Stadien des Menschen First phases of human life 2 cells 4-cells 2. day 8-cells morula compacta 3. day Blastocyst 4.-7. day Early embryo in tubal duct DiakoniePublik 3/2001 Preimplantation genetic diagnosis PGD Gebärmutter Ovar Egg cell Sperm cells Impregnation Development towards blastocyst Withdrawal of a cell Diagnosis of chromosomal defect or genetic disease Implantation of „healthy“ embryo Into uterus „“Defective“ embryos are Discarded and die Stem cells Stem cells in bone marrow Early development of embryo Sperm cell Egg cell Pronucleus Zygote Kryoconservation Multiple fertilization 3. day Totipotency Selection (PGD) Morula germ Withdrawal of embryonic stem cells Blastocyst 5.-7. day Nidation 5.-8.(-14.) Tag 11. Tag End of twinning „primitive streak“ Tissue stem cells 4.-5. day Organogenesis „adult“ Neural duct end of 4th week Brain 8.-12. week Pluripotency Multipotency Dolly the cloned sheep Withdrawal of body cells Depletion Withdrawal of fresh ova Cell membrane Zona pellucida Withdrawal of nucleus Merging of synchronized cells Fusion cell (totipotency) Embryo Implkantation into Foster mother Cloned sheep (genetic copy of cell donor) DiakoniePublik 3/2001 Reproductive Cloning Body cell Donor person to be cloned Nucleus with genetic information Early embryo Donor of egg cells Enucleated egg cell Foster mother Cloned child Implantation of embryo into Uterus of woman Geklonte Orginale DiakoniePublik 3/2001 Germ line engineering Egg cell Sperm cell Fertilization Embryo with „defective“genome Withdrawal of cell Implantation of normal gene Repaired egg cell Becomes embryo Birth of a baby without The new property Human-Genom-Projekt und seine Auswirkungen Founding of Principal Human Rights in a Written Constitution German Basic Law (1949), Article 1 : Die Würde des Menschen ist unantastbar. Sie zu achten und zu schützen ist Verpflichtung aller staatlichen Gewalt. (The dignity of man is untouchable. The state authority is obliged to respect and to protect it.) Constitution of the U.S. (1787): We the people of the United States, in order to form a more perfect union, establish justice, insure domestic tranquility, provide for the common defense, promote the general welfare, and secure the blessings of liberty to ourselves and our posterity, do ordain and establish this Constitution for the United States of America Declaration of Independence of the U.S. (1776): We hold these Truths to be self-evident, that all Men are created equal, that they are endowed by their Creator with certain unalienable Rights, that among these are Life, Liberty and the Pursuit of Happiness Immanuel Kant "Grundlegung zur Metaphysik der Sitten" (1785) "Groundwork to the Metaphysic of Morals" "Der kategorische Imperativ ist also nur einziger und zwar dieser: handle nur nach derjenigen Maxime, durch die du zugleich wollen kannst, daß sie ein allgemeines Gesetz werde". "Der Mensch und überhaupt jedes vernünftige Wesen existiert als Zweck an sich selbst nicht bloß als Mittel zum beliebigen Gebrauche für diesen oder jenen Willen, sondern muß in allen seinen sowohl auf sich selbst, als auch auf andere vernünftige Wesen gerichtete Handlungen jederzeit zugleich als Zweck betrachtet werden". not solely a means, but at the same time an end in itself "Was die Bedingung ausmacht, unter der allein etwas Zweck an sich selbst sein kann, hat nicht bloß einen relativen Wert, d.i. einen Preis, sondern einen inneren Wert, d.i. Würde". not solely a relative value,i.e. a price, but an inner value, i.e. dignity Zweck an sich selbst: end in itself Jeremy Bentham vs. Immanuel Kant Consequentialist vs. Deontological Ethics Extreme positions: Jeremy Bentham (1748-1832): "Principles of Morals and Legislation" 1789 • Utility for producing the greatest happiness (least displeasure) of the greatest number • Judgment of practical value, evaluation of options Immanuel Kant (1724-1804): "Groundwork to a Metaphysic of Morals" 1785 • Fulfillment of the autonomous will of a rational (self-conscious) (human) being • Judgment of obligation, statement of categorical duties (Note: there are theories that found morals outside (or beyond) those principles) What is a Human Being? (in terms of biology) • Numerous definitions in history. Example: Animation (inspiration) at 40th day of pregnancy Modern Convention: • • • Any living entity with the full potential to become a human being beginning with the fertilized egg after conjugation of DNS including totipotent human cell Alternative Convention: Human embryo after nidation into the maternal uterus Attitude Towards Gene Medicine and Artificial Procreation Pragmatic vs. Fundamental Utility vs. Categorical Obligation Jeremy Bentham vs. Immanuel Kant Approach Law Regulating Import of Embryonic Stem Cells (2002) •Import forbidden in principle •Qualified exceptions •Only from „superfluous“ embryos •Superfluous due to reasons not concerning the embryo (exclusion of discarded embryos) •With written informed consent of donors •No material benefits to donors •Only for cell lines established before 2002 (exclusion of „ordered“ stem cells • Law applies to academic and privately funded research Risk Risk = cost of case * probability of event + cost of screening Total genetic risk Each person belongs to a few risk groups for a disease with genetic component Thus in principle everybody should pay a risk surcharge For all persons this will cancel Provided that equity of information is eastablished between insurance and client!
