- While debate on germline gene therapy is still going
on worldwide, geneticists have gone ahead. Prof. Joe Cummins and Dr. Mae-Wan
Ho report on how scientists have sidestepped regulators and created the
first GM human beings, despite fierce public opposition.
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- "Researchers have announced "the first case
of human germline genetic modification resulting in normal healthy children."
Specifically, the researchers transplanted ooplasm from donor eggs into
the eggs of women whose infertility was due to ooplasmic defects. One side
effect of those transplants was the transfer of mitochondria, introducing
new mitochondrial DNA (mtDNA) into the eggs. This news should gladden all
who welcome new children into the world. And it should trouble those committed
to transparent public conversation about the prospect of using "reprogenetic"
technologies to shape future children." So began an editorial in the
April 20 issue of Science magazine [1].
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- Germline gene therapy amounts to changing the gene pool
of the human species by genetic modification of the gametes produced by
individuals. While the pros and cons of GM crops and GM animals are still
being debated, genetic modification of human beings has met with almost
universal condemnation. The prospect of maniacal dictators trying to produce
super races is none too theoretical for those who have lived under the
Nazi regime. And all the more abhorrent that academic science should be
perverted to such ends. Human germline therapy has been shelved, if not
rejected, by most advanced countries, and copious volumes have been generated
by ethicists, philosophers and geneticists from ivy league universities,
telling us why rushing into human germline therapy is not prudent.
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- In spite of those academic reservations and widespread
public concern, a form of germline therapy has already been performed in
New Jersey with little fanfare and no opportunity for public input. A university
laboratory completed an experiment that led to the birth of fifteen apparently
healthy babies as the result of germline gene therapy [2]. But worldwide,
there have already been 30 babies born that have been created in this way.
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- In the US, the Recombinant DNA Advisory Committee (RAC)
was created to oversee and publicly discuss federally funded gene transfer
research. RAC's guidelines say that it "will not at present entertain
proposals" for germline interventions. "Given RAC's de facto
ban on germline intervention, what reasons might have moved highly respected
researchers to announce that they had achieved just that?" Science
magazine asks [1].
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- The experiment was justified on the specious claim that
egg cytoplasm (ooplasm) alone was transferred to the defective eggs of
infertile women which would not allow normal development. In fact the researchers
had assumed mitochondrial defects in the eggs and corrected them by injecting
egg cytoplasm containing presumed normal mitochondria.
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- The RAC dicta were sidestepped on the basis that the
research intervention did not use recombinant DNA (rDNA) technology. .
However, a recent American Association for the Advancement of Science (AAAS)
report [3] already pointed out that RAC's purview is unduly restricted
to techniques (rDNA) that now are more than two decades old. The AAAS working
group argued that if new techniques raise the same ethical concerns as
those raised by "traditional" germline gene therapy, then either
RAC's purview should be expanded to encompass them, or a new, RAC-like
body should be created to oversee them. More importantly, they should be
subject to the same public scrutiny if they raise the same ethical questions
as the traditional germline interventions. Examples of new techniques considered
in the report include the introduction of artificial chromosomes, the use
of oligonucleotides to repair genes in situ--and the transfer of mtDNA.
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- Another caveat is that federal funds were not used in
the ooplasmic transfer experiment, and RAC guidelines are binding only
on those who receive federal funding. However, other privately funded researchers
whose work raises novel issues have consulted with RAC. Given that the
researchers recognized they were engaged in "germline modification",
Science magazine considers it "unfortunate - though perfectly legitimate
- that they did not bring their protocol before RAC" [1].
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- Frankly, that narrow view reeks of academic sleaze. Genetic
recombination involves both gene exchange on a chromosome and re-assortment
of chromosomes. When new mitochondrial DNA was introduced in ooplasm, the
eggs produced were, strictly speaking, made recombinant as the result of
an artificial recombinant DNA technology. The claim that the experiment
falls outside RAC purview is therefore spurious.
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- The apparent cure of infertility by creating heteroplasmic
individuals (those with a mixture of cytoplasm and hence mtDNA) may also
give rise inadvertently to individuals who have the extreme diseases associated
with mitochondrial heteroplasmy, most frequently expressed beyond puberty,
or much later in life.
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- Each mtDNA molecule contains 13 protein-encoding genes
and 24 RNA genes that allow protein synthesis to take place inside the
mitochondria. Transcription and translation of mtDNA is controlled by the
nucleus through the only non-coding region of the mitochondrial genome
(the 1 kb D-loop). The proteins synthesised from the 13 mtDNA genes interact
with more than 60 nuclear-encoded proteins to form the mitochondrial respiratory
chain. The respiratory chain is responsible for extracting energy from
metabolic products of glucose that powers all living activities.
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- Mitochondrial function is, therefore, dependent on the
interaction of many nuclear and mitochondrial genes, and abnormalities
of either nuclear or mitochondrial genome may give rise to mitochondrial
disease. Human cells contain at least 1000 copies of mtDNA. In normal individuals,
all copies of the mtDNA are identical within the coding region. Individuals
with mtDNA disease often exhibit heteroplasmy, ie, they harbour a mixture
of mutated and wild-type (normal) mtDNA. Within single cells, the proportion
of mutated mtDNA must exceed a critical threshold before the cell expresses
a mitochondrial respiratory-chain defect, but the relation between the
proportion of mutated mtDNA and the clinical phenotype of the whole organism
is less clear [4].
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- After fertilisation, sperm mtDNA is degraded. As a consequence,
mtDNA is transmitted exclusively through the mother. Thus, affected men
do not transmit the genetic defect. By contrast, a woman with a heteroplasmic
mtDNA mutation, may transmit a variable amount of mutated mtDNA to her
children. Early in the development of the female germ-line, the number
of mtDNA molecules within each oocyte (developing egg) is reduced before
being subsequently amplified to reach a final number of about 100 000 in
each mature oocyte. This restriction followed by amplification of mtDNA
accounts for the variability between individual oocytes, and the different
proportions of mutant mtDNA seen in the children of a woman [4].
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- Mitochondrial DNA mutations have been linked to seizures,
strokes, optic atrophy, neuropathy, myopathy, cardiomyopathy, sensorineural
hearing loss, diabetes mellitus, and other syndromes. Mitochondrial DNA
mutations may also play an important role in aging, as well as in common
age-related neurodegenerative disorders such as Parkinson'sdisease [5].
Typically, mitochondrial diseases arise by single base pair changes in
the coding regions for proteins or transfer RNA but some arise by short
deletions. More often than not, the disease symptoms are delayed until
puberty or midlife.
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- So, what exactly was the genetic defect corrected in
the GM babies produced [2]? It turns out to be highly ambiguous. The researchers
state, "The basis for this work is the supposition that embryonic
failure may be related to hitherto unknown cytoplasmic pathology."
In other words, the experiments were not based on any scientific finding.
The inheritance of mitochondria was studied after the ooplasmic transplant.
The report focuses on two one-year old children.
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- Significant differences were found in the hypervariable
(D loop) region of the mitochondrial chromosomes between donor and recipient
in both children using DNA fingerprinting technique to identify single
base changes. No other mtDNA region was investigated. It was assumed that
the D-loop mutations were useful as markers, but did not relate to the
dysfunctional ooplasm. In other words, those mutations are assumed to have
no relevance for mitochondrial disease. However, the D-loop mutations observed
in the human recipient eggs were never given a clean bill of health for
the fetus resulting from the eggs. It is clear that the D loop region regulates
replication, transcription and translation. Moreover, those D-loop mutations
in the recipient eggs are flanked by genes, mutations in which are known
to be associated with mitochondrial diseases involving severe neurodegeneration
that appear after the onset ofpuberty. Barritt and coworkers [2] hypothesize
that the defective eggs may be deficient in ATP content, but assumed that
the D loop mutations were unrelated to the presumed ATP deficiency.
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- The researchers appear to have been prepared to risk
the health and long term prospects of infants created in their experiments
even though the oocyte defect was undefined. Were the parents informed
of the lack of fundamental knowledge when they gave their consent?
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- Finally, it seems bizarre that RAC should allow 'recombinant'
to be redefined to exclude the traditionally accepted definition. Certainly,
ooplasm grafting is a rDNA technology; it produces a recombinant mtDNA
genotype differing from either parent. In normal reproduction, mtDNA inheritance
is exclusively maternal.
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- Now is not the time to bring human germline therapy in
through the back door and to promote it through claims of "success"
which may be premature and announced after the experiments. Genetic engineering
may be proceeding along the lines taken in the development of nuclear weapons.
The scientific "elite" may have convinced the political "elite"
that the masses need to be led like cattle to the brave new world.
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- 1. Parens E and Juengst E. Editorials : Inadvertently
crossing the germline barrier. 2001 Science, 2001, 292, 397. 2. Barritt
J, Brenner B, Malter H, and Cohen J. Mitochondria in human offspring derived
from ooplasmic transplantation. Human Reproduction, 2001. 16, 513-6. 3.
Frankel M and Chapman A. Human Inheritable Genetic Modifications: Assessing
Scientific, Ethical, Religious, and Policy Issues (AAAS, Washington, DC,
2000). 4. Chinnery P and Turnbull D. Mitochondrial DNA and disease. Lancet,
1999, 354 suppl 1, 1721. 5. Simon D and Johns D. Mitochondrial disorders:
clinical and genetic features. Ann Rev Med, 1999, 50,111-27
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- For more details contact Prof. Joe Cummins jcummins@uwo.ca
Or Dr. Mae-Wan Ho m.w.ho@i-sis.org
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