I am deeply concerned with the whole GMO protocol.
1 It is all new science and it is playing in the one area in which
Mother Nature is most flexible. This article tells us already how
specific issues are slipping through either by design or by simple
ignorance.
2 Actual empirical testing protocols are primitive and easily end up
been too little too late and at best a band-aid ahead of the real
experiment in which it is fully introduced to Mother Nature. One of
those experiments is going to go badly wrong and show up as
devastating pandemic. We already have the GMO induced Colony
Collapse disease crushing the critical bee industry.
Push back may well see the GMO protocol abandoned at least for the
time been until we know a great deal more. I actually think that
this is now becoming probable in Europe at least.
If a pandemic erupts that wipes out the global corn crop, then we
will see a swift abandonment. The USA is particularly vulnerable as
is China and to a much lessor degree, India. This article pretty
well makes it clear that we are seriously vulnerable when we though
that this was not so.
Regulators Discover
a Hidden Viral Gene in Commercial GMO Crops
MAY 28
hjfoley
How should a
regulatory agency announce they have discovered something potentially
very important about the safety of products they have been approving
for over twenty years?
In the course of
analysis to identify potential allergens in GMO crops, the European
Food Safety Authority (EFSA) has belatedly discovered that the most
common genetic regulatory sequence in commercial GMOs also encodes a
significant fragment of a viral gene (Podevin and du Jardin 2012).
This finding has serious ramifications for crop biotechnology and its
regulation, but possibly even greater ones for consumers and farmers.
This is because there are clear indications that this viral gene
(called Gene VI) might not be safe for human consumption. It also may
disturb the normal functioning of crops, including their natural pest
resistance.
What Podevin and du
Jardin discovered is that of the 86 different transgenic events
(unique insertions of foreign DNA) commercialized to-date in the
United States 54 contain portions of Gene VI within them. They
include any with a widely used gene regulatory sequence called
the CaMV 35S promoter (from the cauliflower mosaic virus;
CaMV). Among the affected transgenic events are some of the most
widely grown GMOs, including Roundup Ready soybeans (40-3-2) and
MON810 maize. They include the controversial NK603 maize recently
reported as causing tumors in rats (Seralini et al. 2012).
The researchers
themselves concluded that the presence of segments of Gene VI
“might result in unintended phenotypic changes”. They reached
this conclusion because similar fragments of Gene VI have already
been shown to be active on their own (e.g. De Tapia et al. 1993).
In other words, the EFSA researchers were unable to rule out a hazard
to public health or the environment.
In general, viral
genes expressed in plants raise both agronomic and human health
concerns (reviewed in Latham and Wilson 2008). This is because many
viral genes function to disable their host in order to facilitate
pathogen invasion. Often, this is achieved by incapacitating specific
anti-pathogen defenses. Incorporating such genes could clearly lead
to undesirable and unexpected outcomes in agriculture. Furthermore,
viruses that infect plants are often not that different from viruses
that infect humans. For example, sometimes the genes of human and
plant viruses are interchangeable, while on other occasions inserting
plant viral fragments as transgenes has caused the genetically
altered plant to become susceptible to an animal virus (Dasgupta et
al. 2001). Thus, in various ways, inserting viral genes accidentally
into crop plants and the food supply confers a significant potential
for harm.
The Choices for
Regulators
The original discovery
by Podevin and du Jardin (at EFSA) of Gene VI in commercial GMO crops
must have presented regulators with sharply divergent procedural
alternatives. They could 1) recall all CaMV Gene VI-containing crops
(in Europe that would mean revoking importation and planting
approvals) or, 2) undertake a retrospective risk assessment of the
CaMV promoter and its Gene VI sequences and hope to give it a clean
bill of health.
It is easy to see the
attraction for EFSA of option two. Recall would be a massive
political and financial decision and would also be a huge
embarrassment to the regulators themselves. It would leave very few
GMO crops on the market and might even mean the end of crop
biotechnology.
Regulators, in
principle at least, also have a third option to gauge the seriousness
of any potential GMO hazard. GMO monitoring, which is required by EU
regulations, ought to allow them to find out if deaths, illnesses, or
crop failures have been reported by farmers or health officials and
can be correlated with the Gene VI sequence. Unfortunately, this
particular avenue of enquiry is a scientific dead end. Not one
country has carried through on promises to officially and
scientifically monitor any hazardous consequences of GMOs (1).
Unsurprisingly, EFSA
chose option two. However, their investigation resulted only in the
vague and unreassuring conclusion that Gene VI “might result in
unintended phenotypic changes” (Podevin and du Jardin 2012). This
means literally, that changes of an unknown number, nature, or
magnitude may (or may not) occur. It falls well short of the solid
scientific reassurance of public safety needed to explain why EFSA
has not ordered a recall.
Can the presence of a
fragment of virus DNA really be that significant? Below is an
independent analysis of Gene VI and its known properties and their
safety implications. This analysis clearly illustrates the
regulators’ dilemma.
The Many Functions of
Gene VI
Gene VI, like most
plant viral genes, produces a protein that is multifunctional. It has
four (so far) known roles in the viral infection cycle. The first is
to participate in the assembly of virus particles. There is no
current data to suggest this function has any implications for
biosafety. The second known function is to suppress anti-pathogen
defenses by inhibiting a general cellular system called RNA
silencing (Haas et al. 2008). Thirdly, Gene VI has the highly
unusual function of transactivating (described below) the
long RNA (the 35S RNA) produced by CaMV (Park et al. 2001).
Fourthly, unconnected to these other mechanisms, Gene VI has very
recently been shown to make plants highly susceptible to a bacterial
pathogen (Love et al. 2012). Gene VI does this by interfering with a
common anti-pathogen defense mechanism possessed by plants. These
latter three functions of Gene VI (and their risk implications) are
explained further below:
1) Gene VI Is an
Inhibitor of RNA Silencing
GENE VI (UPPER LEFT)
PRECEDES THE START OF THE 35S RNA
RNA silencing is a
mechanism for the control of gene expression at the level of RNA
abundance (Bartel 2004). It is also an important antiviral defense
mechanism in both plants and animals, and therefore most viruses have
evolved genes (like Gene VI) that disable it (Dunoyer and Voinnet
2006).
GENE VI (UPPER LEFT)
PRECEDES THE START OF THE 35S RNA
This attribute of Gene
VI raises two obvious biosafety concerns: 1) Gene VI will lead to
aberrant gene expression in GMO crop plants, with unknown
consequences and, 2) Gene VI will interfere with the ability of
plants to defend themselves against viral pathogens. There are
numerous experiments showing that, in general, viral proteins that
disable gene silencing enhance infection by a wide spectrum of
viruses (Latham and Wilson 2008).
2) Gene VI Is a Unique
Transactivator of Gene Expression
Multicellular
organisms make proteins by a mechanism in which only one protein is
produced by each passage of a ribosome along a messenger RNA (mRNA).
Once that protein is completed the ribosome dissociates from the
mRNA. However, in a CaMV-infected plant cell, or as a transgene, Gene
VI intervenes in this process and directs the ribosome to get back on
an mRNA (reinitiate) and produce the next protein in line on the
mRNA, if there is one. This property of Gene VI enables Cauliflower
Mosaic Virus to produce multiple proteins from a single long RNA (the
35S RNA). Importantly, this function of Gene VI (which is called
transactivation) is not limited to the 35S RNA. Gene VI seems able to
transactivate any cellular mRNA (Futterer and Hohn 1991; Ryabova et
al. 2002). There are likely to be thousands of mRNA molecules having
a short or long protein coding sequence following the primary one.
These secondary coding sequences could be expressed in cells where
Gene VI is expressed. The result will presumably be production of
numerous random proteins within cells. The biosafety implications of
this are difficult to assess. These proteins could be allergens,
plant or human toxins, or they could be harmless. Moreover, the
answer will differ for each commercial crop species into which Gene
VI has been inserted.
3) Gene VI Interferes
with Host Defenses
A very recent finding,
not known by Podevin and du Jardin, is that Gene VI has a second
mechanism by which it interferes with plant anti-pathogen defenses
(Love et al. 2012). It is too early to be sure about the mechanistic
details, but the result is to make plants carrying Gene VI more
susceptible to certain pathogens, and less susceptible to others.
Obviously, this could impact farmers, however the discovery of an
entirely new function for gene VI while EFSA’s paper was in press,
also makes clear that a full appraisal of all the likely effects of
Gene VI is not currently achievable.
Is There a Direct
Human Toxicity Issue?
When Gene VI is
intentionally expressed in transgenic plants, it causes them to
become chlorotic (yellow), to have growth deformities, and to have
reduced fertility in a dose-dependent manner (Ziljstra et al 1996).
Plants expressing Gene VI also show gene expression abnormalities.
These results indicate that, not unexpectedly given its known
functions, the protein produced by Gene VI is functioning as a toxin
and is harmful to plants (Takahashi et al 1989). Since the known
targets of Gene VI activity (ribosomes and gene silencing) are also
found in human cells, a reasonable concern is that the protein
produced by Gene VI might be a human toxin. This is a question that
can only be answered by future experiments.
Is Gene VI Protein
Produced in GMO Crops?
Given that expression
of Gene VI is likely to cause harm, a crucial issue is whether the
actual inserted transgene sequences found in commercial GMO crops
will produce any functional protein from the fragment of Gene VI
present within the CaMV sequence.
There are two aspects
to this question. One is the length of Gene VI accidentally
introduced by developers. This appears to vary but most of the 54
approved transgenes contain the same 528 base pairs of the CaMV 35S
promoter sequence. This corresponds to approximately the final third
of Gene VI. Deleted fragments of Gene VI are active when expressed in
plant cells and functions of Gene VI are believed to reside in this
final third. Therefore, there is clear potential for unintended
effects if this fragment is expressed (e.g. De Tapia et al. 1993;
Ryabova et al. 2002; Kobayashi and Hohn 2003).
The second aspect of
this question is what quantity of Gene VI could be produced in GMO
crops? Once again, this can ultimately only be resolved by direct
quantitative experiments. Nevertheless, we can theorize that the
amount of Gene VI produced will be specific to each independent
insertion event. This is because significant Gene VI expression
probably would require specific sequences (such as the presence of a
gene promoter and an ATG [a protein start codon]) to precede it and
so is likely to be heavily dependent on variables such as the details
of the inserted transgenic DNA and where in the plant genome the
transgene inserted.
Commercial transgenic
crop varieties can also contain superfluous copies of the transgene,
including those that are incomplete or rearranged (Wilson et al
2006). These could be important additional sources of Gene VI
protein. The decision of regulators to allow such multiple and
complex insertion events was always highly questionable, but the
realization that the CaMV 35S promoter contains Gene VI sequences
provides yet another reason to believe that complex insertion events
increase the likelihood of a biosafety problem.
Even direct
quantitative measurements of Gene VI protein in individual crop
authorizations would not fully resolve the scientific questions,
however. No-one knows, for example, what quantity, location or timing
of protein production would be of significance for risk assessment,
and so answers necessary to perform science-based risk assessment are
unlikely to emerge soon.
Big Lessons for
Biotechnology
It is perhaps the
most basic assumption in all of risk assessment that the developer of
a new product provides regulators with accurate information about
what is being assessed. Perhaps the next most basic assumption is
that regulators independently verify this information. We now know,
however, that for over twenty years neither of those simple
expectations have been met. Major public universities, biotech
multinationals, and government regulators everywhere, seemingly did
not appreciate the relatively simple possibility that the DNA
constructs they were responsible for encoded a viral gene.
This lapse occurred
despite the fact that Gene VI was not truly hidden; the relevant
information on the existence of Gene VI has been freely available in
the scientific literature since well before the first biotech
approval (Franck et al 1980). We ourselves have offered specific
warnings that viral sequences could contain unsuspected genes (Latham
and Wilson 2008). The inability of risk assessment processes to
incorporate longstanding and repeated scientific findings is every
bit as worrysome as the failure to intellectually anticipate the
possibility of overlapping genes when manipulating viral sequences.
This sense of a
generic failure is reinforced by the fact that this is not an
isolated event. There exist other examples of commercially approved
viral sequences having overlapping genes that were never subjected to
risk assessment. These include numerous commercial GMOs containing
promoter regions of the closely related virus figwort mosaic virus
(FMV) which were not considered by Podevin and du Jardin. Inspection
of commercial sequence data shows that the commonly used FMV promoter
overlaps its own Gene VI (Richins et al 1987). A third example is the
virus-resistant potato NewLeaf Plus (RBMT-22-82). This transgene
contains approximately 90% of the P0 gene of potato leaf roll virus.
The known function of this gene, whose existence was discovered only
after US approval, is to inhibit the anti-pathogen defenses of its
host (Pfeffer et al 2002). Fortunately, this potato variety was never
actively marketed.
A further key point
relates to the biotech industry and their campaign to secure public
approval and a permissive regulatory environment. This has led them
to repeatedly claim, firstly, that GMO technology is precise and
predictable; and secondly, that their own competence and
self-interest would prevent them from ever bringing potentially
harmful products to the market; and thirdly, to assert that only well
studied and fully understood transgenes are commercialized. It is
hard to imagine a finding more damaging to these claims than the
revelations surrounding Gene VI.
Biotechnology, it is
often forgotten, is not just a technology. It is an experiment in the
proposition that human institutions can perform adequate risk
assessments on novel living organisms. Rather than treat that
question as primarily a daunting scientific one, we should for now
consider that the primary obstacle will be overcoming the much more
mundane trap of human complacency and incompetence. We are not there
yet, and therefore this incident will serve to reinforce the demands
for GMO labeling in places where it is absent.
What Regulators Should
Do Now
This summary of the
scientific risk issues shows that a segment of a poorly characterized
viral gene never subjected to any risk assessment (until now) was
allowed onto the market. This gene is currently present in commercial
crops and growing on a large scale. It is also widespread in the food
supply.
Even now that EFSA’s
own researchers have belatedly considered the risk issues, no one can
say whether the public has been harmed, though harm appears a clear
scientific possibility. Considered from the perspective of
professional and scientific risk assessment, this situation
represents a complete and catastrophic system failure.
But the saga of Gene
VI is not yet over. There is no certainty that further scientific
analysis will resolve the remaining uncertainties, or provide
reassurance. Future research may in fact increase the level of
concern or uncertainty, and this is a possibility that regulators
should weigh heavily in their deliberations.
To return to the
original choices before EFSA, these were either to recall all CaMV
35S promoter-containing GMOs, or to perform a retrospective risk
assessment. This retrospective risk assessment has now been carried
out and the data clearly indicate a potential for significant harm.
The only course of action consistent with protecting the public and
respecting the science is for EFSA, and other jurisdictions, to order
a total recall. This recall should also include GMOs containing the
FMV promoter and its own overlapping Gene VI.
Footnotes
1) EFSA
regulators might now be regretting their failure to implement
meaningful GMO monitoring. It would be a good question for European
politicians to ask EFSA and for the board of EFSA to ask the GMO
panel, whose job it is to implement monitoring.
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