Distinguishing between a sick embryo and a pseudoembryo

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Distinguishing between a sick embryo and a
pseudo-embryo
Antoine Suarez, Joachim Huarte, Matthias Lang
Leman Institute for Interdisciplinary Studies
and Swiss Society of Bioethics,
www.embryoperson.org Zürich, July 2005
In collaboration with S. Charrey, M. Durrer, S.
Elavumkudy, P. Lippmann, and T. Pengo.
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Embryo 1.-6. day
In sexual reproduction, each individual inherits
one set of genes from each parent. Normally there
are two copies of each gene one copy in a
maternal chromosome and another copy in the
corresponding paternal one. Note Polar bodies
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Genomic imprinting
The maternal and paternal genomes are not exactly
equivalent, but are endowed with different
imprints, regulating the expression of the genes
during embryonic development. Imprints, or
epigenetic modifications, are chemical changes
to DNA or to chromosomal proteins determining
whether the copy of a gene becomes expressed or
not. They may mark any gene without changing the
DNA sequence, and are transmitted through cell
divisions.

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Oppositely imprinted genes
H19
Igf2
H19
The H19 and Igf2 genes reside on the same mouse
chromosome, and in normal embryos are oppositely
imprinted H19 (red) becomes expressed only from
the maternal chromosome and Igf2 (violet) becomes
expressed only from the paternal chromosome.
Genes not expressed in white.
paternal genome
maternal genome
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Genomic imprinting after fertilization
G1
G2
Igf2
H19
In a normal embryo, resulting through the fusion
of a sperm cell and an egg cell, H19 and other
Genes (G1) become expressed only from the
maternal chromosomes, and Igf2 and other Genes
(G2) become expressed only from the paternal
chromosomes.
paternal genome
maternal genome
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Genomic imprinting influences embryonic
development
In order for normal development to take place, it
seems necessary for the absence of activity of
one gene in a gamete to be counterbalanced by the
presence of the corresponding active gene from
the other gamete. In certain cases, development
fails if there are two active copies of the same
gene (one copy in the maternal and another copy
in the paternal chromosome).

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Embryo-like biological artefacts
Parthenotes cleave and develop like normal
embryos, but die soon after implantation.
A
full-growth ocyte
Artefact containing only maternal genome
Isolate nuclear material from an egg cell (oocyte)
full-growth ocyte
B
Insert nuclear material from oocyte A into
oocyte B
Transferring the nucleus of a full-growth oocyte
(ripe egg cell ) A into another full-growth
oocyte B one constructs a diploid cell, which
contains two sets of chromosomes, all of them
from maternal origin. Such artefacts, often
called parthenotes, can also be produced with two
sets of chromosomes coming from the same oocyte.
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Genomic imprinting in parthenotes 1
G1
In a biological artefact containing only
chromosomes from full-growth (fg) oocytes, H19
and several other genes (G1) become twofold
expressed, whereas Igf2 and several other genes
(G2) remain inactive. Such a mouse parthenote
develops till 12.5-13 days
fg maternal genome
fg maternal genome
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Genomic imprinting in parthenotes 2
G1
G2
Transferring the nucleus of a non-growing (ng)
oocyte (the egg cell of a new born) into a
full-growth oocyte one constructs a diploid cell,
in which the genes G1 and G2 are normally
expressed, but H19 is twofold expressed, whereas
both Igf2 copies remain inactive. Such a mouse
artefact develops till 13.5 days
ng maternal genome
fg maternal genome
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Genomic imprinting in parthenotes 3
G1
G2
H19
By knocking out the gene H19 in the nucleus of
the non-growing oocyte before transfer one
produces an artefact in which H19 is normal
(single) expressed, whereas both Igf2 copies
remain inactive. Such a mouse artefact develops
till 17.5 days
ng maternal genome
fg maternal genome
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Genomic imprinting in parthenotes 4
G1
G2
H19
Igf2
By knocking out the gene H19 and activating the
gene Igf2 in the nucleus of the non-growing
oocyte before transfer one reproduces the genomic
imprinting after fertilization. Such a mouse
artefact develops to birth at 19.5 day
ng maternal genome
fg maternal genome
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The developmental potentiality depends on the
genomic imprinting

• H19 2 ? expressed
• Igf2 2 ? silent
• genes G1 and G2 1 ? expressed

• H19 and several other genes G1 2 ? expressed
• Igf2 and several other genes G2 2 ? silent

• H19 1 ? expressed
• Igf2 2 ? silent
• genes G1 and G2 1 ? expressed

• H19 1 ? expressed
• Igf2 1 ? expressed
• genes G1 and G2 1 ? expressed

12.5-13 days in mouse
13.5 days in mouse
17.5 days in mouse
Birth
Corresponds to about 4-5 week in man
Corresponds to about 5-6 week in man
Corresponds to further than 10 weeks in man
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Which of these developing organisms would be
human persons?

• H19 2 ? expressed
• Igf2 2 ? silent
• genes G1 and G2 1 ? expressed

• H19 and several other genes G1 2 ? expressed
• Igf2 and several other genes G2 2 ? silent

• H19 1 ? expressed
• Igf2 2 ? silent
• genes G1 and G2 1 ? expressed

• H19 1 ? expressed
• Igf2 1 ? expressed
• genes G1 and G2 1 ? expressed

Develops till about 4-5 week
Develops to birth
Develops till about 5-6 week
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Deciding about the moral status of an organism
requires observable biological criteria
The definition of death as brain death, for
instance, clearly establishes a transition point
at which moral status disappears on the basis of
experimental standards. We declare a body brain
dead when it has irreversibly lost the potential
to perform determined spontaneous movements, as
for instance breathing. By assuming that a brain
dead is not a human person, we immediately
associate personhood (or in philosophical terms,
the activity of a human soul) with the neural
activity responsible for spontaneous motility.
By contrast, we do not associate the activity
of the human soul directly with the activity of
the heart, liver or kidneys, even if a lethal
injury to these organs will ultimately also cause
the loss of spontaneous movements. Consequently,
transplantation e.g. of the heart cannot be
considered equal to transplanting the human
soul from one body to another.
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Spontaneous movements
By spontaneous movements we mean movements of the
human body like arm, leg, and lip movements, head
flexion and rotation, eye and breathing
movements. Even if they are often unconscious and
even intentionless, they are potentially
will-directed movements, i.e., they can always be
directed by the will when chosen. In contrast to
these movements of the lips, tongue, eyes,
fingers, etc., it is not possible to use heart
beating to communicate messages. Movements
which are not caused by some stimulus external to
the body, but which are strongly programmed by
biology and cannot be brought under the immediate
control of the will, we call autonomous
movements. Another kind of movement that
escapes the control of the will is a nerve reflex
reaction that has an external cause. Neither
autonomous movements nor reflexive ones are meant
to be connoted by our term spontaneous.
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Spontaneous movements as criterion for defining
the human person
In accord with the definition of death we
consider the biological potential of a human
organism for performing spontaneous movements as
intrinsically united to the human soul and
state Any organism that can develop into a
human body exhibiting spontaneous movements is a
human person
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In humans, spontaneous fetal motility appears
between the 7th. and 15th. week of pregnancy1
Develops further than 10 weeks
Develops to birth
Therefore human embryonic organisms that can
develop further than week 7, or reach birth are
human persons
1 J.I.P de Vries, G.H.A. Visser and H.F.R.
Prechtl., The emergence of fetal behaviour, Early
Human Development, 7 (1982) 301-322.
http//www.mamma.ch/de/hintergrund_embryo.htm
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An organism, which reachs heart beating and blood
circulation, but does not develop beyond is not
a human person
Consider an embryonic organism that would develop
heart beating and blood circulation but would not
unfold the neural activity required for
spontaneous fetal motility. From a moral point
of view such an organism shares the same status
as a brain dead adult (i.e. after irreversible
breakdown of the cortex and the brain stem), and
should not be considered a person. In more
philosophical terms one could say that this
embryonic organism lacks the biological
conditions required for animation through a human
soul, in much the same way as a brain dead adult.
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In humans, heart beating and blood circulation
are well established after the 4 pregnancy week
fg/fg parthenote
development till about 4-5 week
Therefore fg/fg parthenotes, which can reach the
4-5 pregnancy week, but do not go beyond are not
human persons
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Further experiments are needed to decide whether
ng/fg human parthenotes (H19/Igf2 mutants) are
human persons or not
ng/fg parthenote

• it would be necessary to show through
  ultrasonography that ng/fg mouse parthenotes do
  not really reach spontaneous fetal motility.
• one should demonstrate through so called gene
  expression phenotypic analysis that two active
  copies of H19 together with two silent copies of
  Igf2 causes defects in the fetus brain itself.
• One should confirm these observations in primates
  too.

development till about 5-6 week
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How to decide about organisms which do not reach
heart beating?
The fact that upon implantation in a properly
functioning uterus an embryonic organism does not
reach heart beating is not a sufficient condition
for concluding that such an embryonic organism is
not a person. Indeed, it could be a human
person with a severe congenital defect, who could
be rescued through an appropriate therapy.
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Human Id mutants, even if they do not reach
heart beating, are sick persons
After knockout of several Id genes in mice the Id
mutants obtained through fertilization die at
about day 11.5 of gestation. Observations suggest
that a defective heart is the primary cause of
this mid-gestation lethality. The Id mutants can
be rescued by the injection of a low number of
wild-type embryonic stem cells into mutant
blastocysts.
Id mutant
Human Id mutants would be comparable to persons
carrying a heart lethal injury, and their
restoration comparable to heart transplantation
development till 11.5 days in mouse
about 3-4 week in man
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Good indicators to ascertain the moral status
Defects that tolerate healthy development till
reaching heart beating and blood circulation, but
inhibit the emergence of the brain activity
triggering fetal motility are good indicators for
ascertaining the moral status of an organism. We
denote such defects through the
abbreviation SIENA (Specific Inhibition of the
Emergence of Neural Activity)
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Principles to decide about the moral status of
a human organism

• Any abnormality including one or several SIENA
  defects renders an organism inadequate to be
  animated by a human soul. We denote these
  inherently non-viable embryonic entities as
  pseudo-embryos. A SIENA organism or pseudo-embryo
  could be compared to a body without brain but
  with the other organs working well.
• In absence of any SIENA defect one must conclude
  to the presence of a human soul, and consider the
  embryonic organism as a true embryo with some
  severe congenital illness. It is the case of the
  Id mutants.
• If there is doubt about whether an embryonic
  organism contains a SIENA-defect, one cannot
  exclude the presence of a human soul.

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End