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Scientific facts help clarify the debate
Six years after publishing the experiments of Ian
Wilmut and his associates (Nature, 1997, 385: 810-813) that led
to the birth of the first cloned mammal via somatic cell nuclear
transfer (SCNT), human cloning continues to be the object of
unremitting biological research, lively philosophical, ethical and
juridical conjecture, and heated public debate. The more realistic
perspective of restricting cloning to certain laboratory or
specially-bred animals, or to a limited number of wild species nearing
extinction, seems to have averted the initial spectre of a dangerous
technological interference by SCNT due to biodiversity, the process of
natural selection and the balance among the species.
Thus, most scholars and citizens today are prepared
to accept the cloning of animals for purposes such as the pre-clinical
experimentation of drugs and transgenesis related to the etio-pathological
study of certain diseases and the production of bio-molecules for
medical treatment (proteins, for example, such as the α-1-antitrypsin,
and coagulation factors VII and VIII), and tissue and organs destined
for surgical therapy. On the other hand, there is a deeply disturbing
possibility —
reinforced at times by non-documented scientific information
disseminated by the media —
that cloning by SCNT has been or may be applied to humans, with the
a-sexual reproduction of human embryos for research or for transfer to a
uterus for development and birth.
After a period of animal experimentation, which not
only enabled the cloning technique to be perfected but also paved the
way to acquiring the first notions of its effects on the growth and
survival of the embryo and fetus, the gestation process and the
perinatal and postnatal physio-pathological structure of certain cloned
mammals, it seems appropriate to return to the serious issue of human
cloning and supply additional facts for a deeper philosophical
knowledge, moral assessment and juridical consideration. Background is
needed because of an improper and deceptive use in public debate of the
"so-called" distinction between "reproductive" and
"therapeutic" human cloning. The terms were introduced to
differentiate between two intended "uses" of one and the same
cloning process, SCNT, with the same result: a human embryo.
"Reproductive" cloning refers to the
transfer of a cloned embryo to a uterus and its subsequent development
to birth; "therapeutic" cloning aims at harvesting autologous
embryonic stem cells from the internal cellular mass of the cloned
embryo, thus destroying it for therapeutic and research reasons when it
has reached the blastocyte stage (about five days after SCNT). In fact,
cloning any organism is "reproductive" in the etymological
sense, being "re-produced": when successful, "it produces
again" an organism of the same species at the initial stage of its
embryonic growth. Unless there is a wish surreptitiously to introduce
the idea that a human embryo in the initial phases of growth is not a
living organism at the beginning of its life-cycle (contrary to
experience, reason and scientific literature from more than a century of
biological study), whatever use this "product of human
cloning" may be intended for, it cannot alter the biological and
ontological aspect proper to the "product", nor the moral
aspect of the act of cloning that must first be considered
independently. The distinction between "reproductive" human
cloning and "therapeutic" cloning that claims to have an
ethical and juridical dimension confuses the purpose of the procedure
with the actual question of the act.
Also misleading is the conviction that
"therapeutic" cloning's "final result" is merely the
cultivation in vitro of embryonic stem cells (a cell clone),
whereas "reproductive" cloning results in a child (an
individual born from developing an embryonic clone-organism). The
argument forgets that the clone of human stem cells derives from a
cloned human organism in the embryonic phase of development which, had
it been transferred to a uterus instead of being destroyed, could have
developed into a fetus and later, a new baby. Autologous embryonic stem
cells in current or planned research are the secondary product of
cloning; the first, in every case, continues to be the embryo.
As in the case of other biotechnological
interventions in human procreation, "a preliminary point for the
moral evaluation of such technical procedures is constituted by the
consideration of the circumstances and consequences which those
procedures involve in relation to the respect due to the human
embryo" (Congregation for the Doctrine of the Faith, Donum Vitae,
II). Among these, particularly important for moral judgment are the high
percentages of failure in light of live births that are so far recorded
in animal cloning, and the effects of SCNT on the somatic integrity and
health of the cloned animal.
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A first conclusion emerging from the experimental
data is the significant variability in quality of the results obtained
by applying the same or a similar cloning technique to animals of
different species, even when the work is done by the same team of
researchers. Despite repeated attempts, it has not yet been possible to
obtain from the intra-oocite transfer of the nuclei of post-fetal cells
the birth of rats, dogs, horses or monkeys (Y. Tsunoda and Y. Kato, Differentiation
2002, 69: 158-161). Even the recent cloning of a mule was possible only
due to using fibroblasts from fetuses at the 45th day of development, to
whose nucleus was transferred a horse oocite whose nucleus had
previously been removed. This suggests that the technical possibility
that human cloning via SCNT may effectively lead to human birth should
not be taken for granted.
In every case, the attempts needed to verify this
hypothesis are also unjustifiable from the ontological and professional
viewpoint of the biomedical researcher, with regard both to the negative
outcome so far obtained on the animal model closest to the human being
that was used (Macacus rhesus monkey) and because of the high
number of oocytes needed (which could be obtained only by
hyperstimulating the ovaries of numerous volunteers, a pharmacological
process not exempt from gynaecological complications), and above all,
because of the destruction of human embryos to which this would lead:
"To use human embryos or fetuses as the object or instrument of
experimentation constitutes a crime against their dignity as human
beings having a right to the same respect that is due to the child
already born and to every human person" (Donum Vitae, I, n.
4).
A second aspect of cloning concerns the procedure's
effectiveness in mammals born via SCNT using the nuclei of post-fetal
cells: the sheep, cow, rat, pig, goat and recently, the rabbit and cat.
In these species the effectiveness of cloning from nuclei of adult
animal cells is minimal. Typically, less than 1 percent of embryos
resulting from SCNT and 4 percent of those transferred to the uterus
achieve proper prenatal development and birth (I. Wilmut et al., Nature
2002, 419: 583-586). In the case of the rhesus monkey,
cloning from nuclei of adult tissue cells has so far failed, but using
those from embryos with eight cells (more easily reprogrammed, with
better results in other species) has led to the birth of only two
animals out of 53 cloned embryos transferred to a uterus (0.4%: D.P,
Wolf et al., Biology of Reproduction 1999, 60: 199-204).
This tiny number is not only due to the greater
difficulty in the in vitro culture of agamic embryos, the
percentage of whose survival and growth is in any case lower than that
of embryos reproduced by fertilization; it is also linked to a high
abortion rate after transfer and implantation in the uterus. In the
human being, as in the animal, spontaneous abortions also occur in a
number of pregnancies that result from natural conception or from in
vitro fertilization (IVF); but whereas in these pregnancies the loss
of the embryo occurs most frequently in the first three months, in the
case of cloning there is a high risk of abortion throughout the
gestation period; this is associated with a consistent perinatal and
neonanal mortality rate ("many cloned animals die within 24 hours
of birth": I. Wilmut et al., a.c., p. 583). A
pathology of the placenta, including vascular insufficiency, is the
chief cause of the loss of cloned sheep and cow fetuses in the first
months of gestation (J.R. Hill et al., Biology of Reproduction
2000, 63: 1787-1794). In the case of rat clones, placenta-megaly caused
by the expansion of the layer of the spongio-trophoblast is frequent (S.
Tanaka et al., Biology of Reproduction 2001, 65: 1813-1821).
These and other complications, such as toxemia, observed in pregnancies
via SCNT are a cause of fetal stress and endanger the health and life of
the mother. For example, in a study by J.R. Hill and his collaborators (Theriogenology
1999, 51: 1451-1465), four of the 13 pregnant cows and their fetuses
died from complications towards the end of gestation. The consideration
that human abortion in the later stages of pregnancy is associated with
an increased likelihood of maternal disease and mortality leads to the
presumption that human cloning "would also entail a high risk for
the health of both the fetus and child, as well as of the mother"
(National Academy of Sciences [USA], Scientific and Medical Aspects
of Human Cloning, National Academy Press, 2002, p. 40).
Thus, a further biological and clinical problem
connected with SCNT emerges. If it is recorded —
as certain champions of research into human cloning claim —
that many of the animals cloned so far "appear healthy and
normal" (according to the review of 335 cases published by J.B.
Cibelli et al. [Nature Biotechnology 2002, 20; 13-14], so would
the 77 percent of those that survived the first week of extrauterine
life), yet "a high incidence of congenital abnormalities is found
in comparison with normal reproduction", which are revealed before
and after birth, or even only at an older age (J.B. Cibelli et al., op.
cit, p. 13; cf. also the National Academy of Sciences [USA], op.
cit., pp. 39-42; I. Wilmut et al., op. cit., p. 583;
and J.R. Hill, Differentiation 2002, 69: 174-178). Among the
defects observed are: excessive birth weight (frequent in the cow and
goat), certain pulmonary pathologies (respiratory insufficiency in the
sheep, cow and rat; pulmonary hypertension in the cow), immune system
deficiencies and infections (cow, sheep), articulatory diseases
(juvenile arthritis in the sheep; arthrogryposis in the cow) and obesity
not associated with hereditary factors (rat). The LOS (Large Offspring
Syndrome) phenotype, characterized at birth by hypertrophy of the
placenta and weight excess in the newborn offspring, has been observed
in many cloned cattle, rats and sheep, but is also sporadically present
in certain animals born by IVF. In the human, it is well known that
excessive birth weight increases risk of disease.
Research into the causes of the high incidence of
intrauterine deaths and abnormalities among SCNT-cloned animals is only
in its early stages, but several explanations have been proposed that
appear to correspond with the experimental data available. Some
specialists believe the "problems associated [with the failures of
cloning] are not all of a technical nature... and it is not clear which
of them could be eliminated by an improvement in technique" in the
selection and cultivation of the donor somatic cell, of the nuclear
transfer and of the activation of the oocite whose nucleus has been
removed after transfer (D. Solter, Nature Reviews Genetics 2000,
1: 199-207, p. 204). The microscopic observation of cloned bovine
blastocytes has made it possible to identify a relationship between the
number of cells in the embryoblast and those in the trophoblast, higher
in comparison with the embryo that originated from fertilization, and it
is known that fewer cells in the trophoblast diminish the embryogenetic
potential and reduce viability after implantation, probably because of
abnormal placenta development. At the molecular level, the expression of
certain genes that is proper to the trophectoderm is altered by SCNT
cloning (C. Wrenzycki et al., Biology of Reproduction 2001, 65:
309-317); that of gene MHC-I in particular could cause an endometrial
immunological response with an abortive effect (J.R. Hill et al., Biology
of Reproduction 2002, 76: 55-63).
The result of cloning depends on the satisfactory
epigenetic reprogramming of the nucleus, which must be converted from a
specific tissue to a totipotent state. The donor nucleus must interrupt
the programme of genetic expression and rapidly activate the one
required for the embryo's development. Correct epigenetic reprogramming
provides for the remodelling of the structure of the chromatin, an
extended demethylation and remethylation of the DNA, and other
precocious embryonic-genetic phenomena. If some of these processes do
not occur completely and/or in the time and order required, the embryo's
development is jeopardized at one or other of its critical stages (the
so-called "epigenetic check-points"), with effects that
could also be manifested later in the individual's life. Errors in
epigenetic reprogramming, among other things, were observed at the level
of the state of methylation of the DNA (for example, in blastocytes and
cloned bovine fetuses). Defects were also found in the
post-transcriptional regulation of the genes.
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Over and above any further and necessary
anthropological or moral considerations, it will be impossible in an
ethical evaluation of experimental research in the reproduction of human
individuals via cloning to ignore evidence of development that is
abnormal or impeded by certain pathologies in many animals cloned by
SCNT. "There is no doubt", Pius XII recalled with regard to
therapeutic experimentation, "that with a new method, still
insufficiently tested" on animals, "before accepting the use
of new methods as morally licit, it is impossible to demand the
exclusion of every danger, of every risk. This goes beyond human
possibilities, it would paralyse all scientific research and frequently
be to the detriment of the patient.... Nonetheless, as our explanations
have shown, there is a degree of danger that morality cannot permit....
This way of proceeding [in the presence of a danger to the subject]
cannot be established as a rule of conduct in normal cases" (Address
to Participants in the Premier Congrès International d'Histopathologie
du Système Nerveux, 14 September 1952, in: AAS 44 [1952]
779-789, pp. 788-789), not even when the health of the sick person for
whom an experimental treatment is recommended is at stake. It must be
limited to "desperate cases, when the sick person will die if
nothing is done, and when a medicine, means or operation exist which,
without excluding every danger, may yet have a certain probability of
success" (Address to the Participants in the VIII Congrès de
l'Association Médicale Mondiale, 30 September 1954, in: Discorsi
e Radiomessaggi 16 [1955] 167-179, p. 172).
This applies a fortiori to scientific research
on an unborn human being carried out for purposes other than treating a
life-threatening disease that personally afflicts him: cloning certainly
cannot qualify as "a strictly therapeutic intervention whose
explicit objective is the healing" (John Paul II, Address to the
35th General Assembly of the World Medical Association, 29 October
1983; ORE, 5 December 1983, p. 10) of the person subjected to
experimentation, nor for "his individual survival", a
condition for which "one must uphold as licit procedures
carried out on the human embryo" (Donum Vitae, I, n. 3).
Even the Helsinki Declaration —
which inspires the conduct of specialists of every culture and religious
orientation since 1964 —
after recalling that "medical research which involves human
subjects... must be based on a complete knowledge of scientific
literature, on other pertinent sources of information and on adequate
laboratory experimentation, and, where appropriate, on animals",
says that in this same research, "it is the duty of the doctor to
protect the life, health, privacy and dignity of the human
subject". Indeed, "in research on human subjects
considerations associated with the well-being of the human subject must
take precedence over the interests of science and society" (52nd
General Assembly of the World Medical Association, Declaration of
Helsinki: Ethical Principles for Medical Research Involving Human
Subjects, 6th rev. ed., Edinburgh, 2000).
The sense of responsibility mentioned by the Declaration
is also echoed by some distinguished researchers in the field of animal
cloning. Cloning "is a somewhat inefficient and unpredictable
process" (W. Shi et al., Differentiation 2003, 71: 91-113,
p. 91). SCNT "is currently an unreliable technique. We therefore
consider that the technology of nuclear transfer should not be used in
human beings or in therapeutic application until its technical
reliability has been confirmed" (Y. Tsunoda and Y. Kato, op.
cit., p. 160); indeed, it would "be unethical to attempt to
produce and transfer cloned human embryos when it is well known that
with this same procedure in animals there is a high risk of some fetal
abnormality" (J.R. Hill, op. cit., p. 175). "We
regard as dangerous and irresponsible attempts to clone human beings at
a time when the scientific aspects of cloning by nuclear transfer have
not been clarified" (R. Jaenisch and I. Wilmut, Science
2001, 291: 2552).
See Part 2.
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