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[SANET-MG] gm food animals part 3
gm food animals part 3
C. Outstanding Safety Issues
Food derived from genetically modified animals pose several kinds of
health risks, whether heritable or not, and we do not recommend using
them as food unless and until these risks have been assessed, and
comprehensive studies show that they are safe beyond reasonable doubt.
The health risks of food derived from genetically modified animals come
from the specific proteins encoded by the transgenes, from the
transgenic nucleic acids and vectors used for genetic modification, and
from unintended effects of transgenesis and the cloning procedures used
to produce a herd of transgenic animals, as the transgenic animals are
often sterile or else do not breed true [79].
Non-heritable traits, in particular, include potent synthetic antigens
for vaccination and powerful immune regulators with well-described side
effects, while both heritable and non-heritable traits include growth
hormones. The ingestion of foods with growth factors, vaccine antigens
or immune regulators is likely to have untoward impacts on the immune
system and development of human beings, especially the young.
Many of the genes used to create transgenic food animals are synthetic
approximations of the original gene, but deemed, mistakenly, to be
“substantially equivalent” to the natural genes. The synthetic genes
contain DNA sequences that have never existed in evolution, and by no
stretch of the imagination can they be presumed safe.
Synthetic genes are used, first of all, because bacterial genes are not
readily translated in animals and plants. Bacteria use different codons
for the same amino acids (codon bias), and so the gene sequence has to
be modified to allow for that. Transgenes are often composites of
different genes. For example, a synthetic transgene was made up of an
antibacterial gene from Staphylococcus (lyphostatin) joined to a gene
from a Streptococcus bacteriophage (virus of bacteria) encoding
endolysin, which dissolves bacteria. The synthetic composite gene was
used to modify cows, so they would produce milk that kills bacteria [80].
One main problem discussed was allergenic potential of the protein in
milk. Proponents assured us that the cows modified with the synthetic
gene were unlikely to be allergic to the toxin because it is a part of
their genome, and thus recognized as self. But they failed to mention
that children drinking the milk would not recognize the protein as
‘self’, and might well mount immune reactions against the protein,
including allergy.
Efforts were made to ‘humanize’ transgenic proteins by altering the
genes specifying a protein’s glycosylation pattern to avoid immune
reactions including allergy (allergy sites on proteins often have
specific glycosylation), but that approach was only partly effective
[81-83]. In view of the recent finding that a normally harmless bean
protein turned into a potent immunogen when transferred to pea [82, 83]
(Transgenic Pea that Made Mice Ill), there is a case for banning all GM
food products until and unless they can be proven safe by adequate
tests. This applies all the more so to transgenic animal food products,
especially milk, which is consumed predominantly by infants and children.
The profligate use of nucleic acids (RNAs and DNAs) in livestock is a
source of deep concern, as it is already well known that they are to
varying degrees capable of horizontal gene transfer and recombination
with attendant risks of creating new viruses and bacteria that cause
diseases, and of triggering cancer by integrating into genome sites that
activate oncogenes as gene therapy clinical trials have made all too
clear [84] (Gene Therapy Woes). Similarly, RNAi overload proved lethal
to mice [56]; and it is not safe to presume that the RNAi used to modify
animals will not affect those consuming the treated animals.
The dangers of genetic engineering, especially the use of recombinant
viral vectors and bacteria have been recognized by genetic engineers
themselves before the lure of commercial exploitation swept aside these
concerns [85] (Gene Technology and Gene Ecology of Infectious Diseases).
We have continued to warn of the dangers of environmental releases of
genetically modified nucleic acids in subsequent years, and constructs
with recombination hotspots such as viral promoters [86-89] (Slipping
through the regulatory net; Cauliflower Mosaic Viral Promoter - A Recipe
for Disaster?; Hazards of Transgenic Plants Containing the Cauliflower
Mosaic ...; CaMV 35S promoter fragmentation hotspot confirmed, and it is
...)
There have been no studies addressing the unintended changes of genetic
modification in transgenic animals, which may well create unexpected
toxins or immunogens [79] (Fatal Flaws in Food Safety Assessment:
Critique of the Joint FAO ...). Similarly, the cloning process is
already known to result in unintended gross morphological as well as
genetic defects [90] (What's Wrong with Assisted Reproductive
Technologies?) that may compromise the safety of transgenic meat.
Comments to the Proposed Draft Guideline for the Conduct of Food Safety
Assessment of Foods Derived from Recombinant - DNA Animals
We comment first on matters raised by codex and then some issues not
discussed in the Codex food safety assessment.
Codex QUESTIONS FOR AN EXPERT CONSULTATION
Marker and Reporter Genes
What developments have occurred in the development and use of reporter
and selectable marker genes?
Selectable markers are commonly employed with both heritable and
non-heritable genetic modifications of animals. Common reporter genes
are green fluorescent protein, beta-glucuronidase and beta-galatosidase.
Selectable markers have included herbicide tolerance genes, although
they are not widely used.
Are there non-antibiotic resistance marker or reporter genes that have
been demonstrated to be safe to humans in food products, and if so, what
are they?
A far as we know, none of the non-antibiotic resistance marker or
reporter genes has been demonstrated as safe to humans in food products,
while at least one of them, beta-glucuronidase, was found to have amino
acid similarities to known allergens [81] (Are Transgenic Proteins
Allergenic?).
In prokaryote vectors and in applications such as non-heritable
(epigenetic) modifications or in cloning animals from modified tissue
cells, antibiotic resistance markers are commonly employed.
With prokaryote expression systems for producing pharmaceuticals, the
most common way to achieve selection in the absence of antibiotics is
via complementation of an essential gene expressed in a plasmid vector
in a strain with a defect in the same essential gene. Several authors
have used the dapD gene, which has a role in the lysine biosynthetic
pathway and in cell wall assembly. Cobra Therapeutics proposed a very
promising system, the ‘operator repressor titration for antibiotic-free
plasmid maintenance’, in which plasmid loss induces the down regulation
of the essential dapD gene, and thus the death of the bacteria. Other
systems such as pCOR, based on the complementation of an amber mutation,
have also been established. Nevertheless, the requirement for a minimal
medium for culture means these systems are less likely to be used for
production depending on over-expression. The various
complementation-based expression systems have the common drawback of
being strain dependent, as genetic knockout or modification of an
essential gene is not easily transferable from one strain to another and
has to be done independently [91].
A luminescence gene cassette from the Photohabdus luminescens bacterium
(an insect pathogen) provides a light emitting tracer gene that can be
used with both prokaryote and eukaryote organisms [92].
When removal of specific DNA sequences is desired, are reliable and safe
techniques available to do this on a routine basis?
There is one system, the Crelox, used almost exclusively with both
prokaryotes and eukaryotes. Lox sites are signals for site-specific
recombination by the Cre recombinase enzyme. A pair of lox site flanks a
marker gene or any gene to be removed. The Cre recombinase is driven by
a promoter designed to respond to a signal such as an antibiotic or
drug. The main problem with its use in higher animals and plants is that
the genomes of the higher organism contain cryptic lox sites that are
recognized by Cre recombinase, causing chromosomal instability in the
genome. The Cre recombinase is effectively genotoxic [93, 94]
(Terminator Recombinase Does Scramble Genomes) and should not be used.
Non-heritable Applications
Are there relevant differences from a food safety perspective between
animals with heritable and nonheritable traits, and if so, what are they?
Our review of the non-heritable techniques includes the use of DNA
plasmids and viral vectors in both vaccination and in gene therapy to
improve meat production or quality. It may appear that the food safety
issues of heritable transgenic traits and non-heritable traits are
different. Non-heritable traits are mainly based on DNA plasmids,
bacterial vectors or viral vectors that do not theoretically integrate
into the germline genome, though there is always a small probability
that any DNA introduced into an organism may integrate into the germline
genome, as the germ cells are not separated from somatic cells by any
real physiological barrier that prevents horizontal gene transfer. On
account of the unjustified presumption that the foreign genetic material
will not be incorporated into the germline, there is a tendency for
relaxed regulation, which is equally unjustified.
Many of the recombinant DNA plasmids, bacterial vectors or viral vectors
have been subject to clinical trials or even approved with little
fanfare and public notification. It has been presumed that the
recombinant genes and their protein products are not present in the milk
or meat of treated animals but there is little published information to
support that assumption, and that is perhaps the main danger.
Are there specific food safety questions (e.g. with regard to types of
vectors) that should be considered relative to the assessment of safety
of food from animals containing heritable versus non-heritable traits?
We have stressed in our review that the both heritable and non-heritable
modifications pose the same kinds of risks, from the products of the
transgenes, from the nucleic acids and vectors used in genetic
modification, and from unexpected effects of transgenesis, and in the
case of heritable modifications, from the cloning procedures.
Non-heritable traits, in particular, include potent synthetic antigens
for vaccination and powerful immune regulators, while both heritable and
non-hertable traits include growth hormones. These contaminants in foods
are likely to have adverse impacts on the immune system and development
of human beings, especially the young.
There does not seem to be much published information on the fate of
vectors or the transgenes in the treated animals, or the potential for
horizontal gene transfer and recombination to create new pathogens. RNAi
overload proved lethal to mice; and it is not safe to presume that the
RNAi used to modify animals will not affect those consuming the treated
animals.
Non-heritable genetic modifications are more threatening than heritable
modifications because of its widespread use without the necessary risk
assessments. It is also highly likely that meat or milk of recombinant
animals will not even be labelled in the market, as they do not fall
under the rubric of genetic modification.
The profligate use of nucleic acids (RNAs and DNAs) in livestock is a
source of deep concern, as it is already well known that they are to
varying degrees capable of horizontal gene transfer and recombination
with attendant risks of creating new viruses and bacteria that cause
diseases, and of triggering cancer by integrating into genome sites that
activate oncogenes.
There have been no studies addressing the unintended changes of genetic
modification in transgenic animals or of cloning, which may well create
unexpected toxins or immunogens.
Substantial equivalence has no value and is misleading
The Codex Draft Guideline states:” The concept of substantial
equivalence is a key step in the safety assessment process.”
We take issue with that statement. “Substantial equivalence” is often
used as a starting point to structure the safety assessment of a new
food in the most undiscerning and reductionist way. For example,
comparisons are made in the gross composition of proteins, carbohydrates
and fats, or in amino acid compositions, which generally show little or
no difference; and so it allows the proponent to focus on the transgene
product(s) only [79]. Moreover, the comparators are completely
arbitrary. Instead of comparing the transgenic variety with the variety
from which it has been derived, companies have been allowed to compare
the transgenic variety with the entire species, or indeed with whole
category of foodstuffs from many different species, as in the case of
edible oils for example.
Although there have been attempts to improve on establishing substantial
equivalence by incorporating profiles of total protein, metabolites and
transcripts, the technical hurdles involved in comparing and
interpreting patterns are insurmountable, and no official requirements
are enforced. In this way, unintended, untoward effects of the
modifications will not be revealed unless specific tests other than
those used for establishing substantial equivalence are carried out.
Examples are tests for toxicity, allergenicity and immunogenicity.
Substantial equivalence therefore has nothing to say about the safety of
the transgenic food product, and it would be highly misleading to assume
it does.
Synthetic genes are not substantially equivalent to the natural
One important fact ignored by the Codex guidelines, which also disposes
of the concept of substantial equivalence is that the recombinant
animals are constructed using synthetic versions of natural genes that
often involve composites of different genes, with different nucleic acid
sequences as well as changes in amino acid sequence. The changes in
nucleic acid sequence will lead to differences in the recognition of the
gene by nucleosomes and histones. Changes in amino acids will give
proteins with different conformations that would affect the proteins’
interactions with other proteins, and are likely to be regarded as
foreign by the host’s immune system, as well as by humans eating the
transgenic food. Furthermore, these proteins specify potent antigens,
growth factors, cytokines or other signal proteins that have potent
biological effects and can in no way be regarded as safe.
Transgenes exchanged between closely related species are not
substantially equivalent
Even when genes are transferred between closely related species,
glycosylation patterns change during protein processing, and could have
catastrophic consequences for the human consumer [82, 83] (as discussed
in the literature review). Codex should abolish the discredited concept
of substantial equivalence once and for all, in recognition that it is
highly misleading when used as a key concept in safety assessment.
We do not recommend using genetically modified animals and animal
products as food, until and unless they can be proven to be safe by
comprehensive safety evaluations, whether the genetic alterations are
heritable or non-heritable.
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