Living is a risky endeavour - less so through genetic medicine?

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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!
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