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2-Plants: Some scientific thoughts on the principle of substantial equivalence



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TITLE:  The Promise of Plant Biotechnology -
        The Threat of Genetically Modified Organisms
SOURCE: Patrick Brown, University of California
DATE:   July 2000

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The Promise of Plant Biotechnology - The Threat of Genetically 
Modified Organisms

July 2000

Patrick Brown
Professor
College of Agriculture & Environmental Science
University of California
Davis, CA 95616


Crop cultivars developed using recombinant-DNA technologies (rDNA 
crops) have been rapidly adopted by agricultural producers in the 
United States; and until recently, foods derived from these crops 
have been tacitly accepted by US consumers. In contrast, many 
European consumers have shown a marked resistance to these 
technologies, which, in turn, has resulted in the passage of trade 
restrictions and of laws that limit the import, growth or use of rDNA 
crops throughout much of Europe. The public uproar in Europe, and the 
protests surrounding the World Trade Organization meeting in Seattle, 
has now raised the awareness of many in the USA and given birth to a 
vocal and growing group of concerned consumers.

The intensity of the current debate has surprised many in the 
scientific community and has escalated into a highly polarized and 
increasingly antagonistic debate. Scientists, and the professional 
organizations that represent them, have been publicly supportive of 
this technology and often dismissive of public concerns. Most 
scientific comment suggests that 'education' is the key to gaining 
the needed acceptance, while almost no comment has recognized or 
addressed the fears of the public. Those who oppose rDNA technology 
interpret the apparent willingness of the US scientific community to 
embrace this new technology, while failing to adequately address the 
potential risks, as a betrayal of public trust.

Public uncertainty has resulted in the loss of markets, and will 
increasingly do so, for the current generation of rDNA crops and 
foods. Though this is clearly of substantial economic concern, by far 
the most significant consequence of public concern is the threat that 
this conflict poses for the entire field of plant biotechnology, 
which holds far greater promise of human benefit than that offered by 
any existing rDNA crop. The loss of this technology through careless 
and premature implementation would be truly devastating to the goal 
of developing more abundant and nutritious foods in an 
environmentally sensitive fashion.

This issue requires immediate and thoughtful attention from plant 
scientists. We must recognize that our knowledge of the processes 
that regulate gene incorporation and expression are in their infancy 
and that our capacity to manipulate the plant genome is crude. Given 
this current lack of understanding it is certainly possible that the 
current regulatory safeguards are inadequate and may not be offering 
sufficient protection against inadvertent creation of health and 
ecological problems.

Since the public education and research system is based upon a 
foundation of public trust, it is essential that we recognize and 
admit the unknowns associated with molecular biology and act with 
caution and integrity.

The following text describes some of the uncertainties associated 
with rDNA technology and illustrates how the scientific community's 
defence of the current generation of rDNA crops represents a 
substantial threat to the future of this promising new technology.


Are the Current Generation of rDNA Crops, and the Regulatory System 
that approved them, Scientifically Defensible?

In 1989 the National Research Council, following extensive scientific 
review, publicly concluded that crops derived from rDNA techniques do 
not differ substantially from those derived using traditional 
techniques. This conclusion forms the basis for current FDA policy 
that regulates the production and use of rDNA crops and foods. This 
conclusion is based upon the principle of "substantial equivalence" 
which states that the introduction of a gene of known and safe 
function into a crop of known characteristics is technologically 
neutral, hence the resulting crop can be presumed to be safe and is 
not subject to mandatory testing prior to release or use in foods. As 
this principle is central to the scientific and regulatory acceptance 
of this technology it deserves careful examination.


Is There Equivalence between rDNA and 'Traditional' Sexual Gene 
Transfer?

To adequately compare these technologies it is essential that each is 
well characterized and understood. The molecular processes that 
control gene incorporation and expression following a normal sexual 
crossing event, however, are only poorly understood and the extent of 
our ignorance is further revealed weekly as new processes involved in 
the regulation of gene expression in plants are determined. The 
inadequacy of our understanding is well illustrated by the host of 
genetic phenomena (such as co-suppression, intron-mediated 
enhancement, transcriptional regulation, protein-gene interactions 
etc) for which we have essentially no mechanistic understanding. Our 
knowledge of these processes is clearly in its infancy and few would 
claim that we understand more than a small percentage of the 
processes regulating sexual reproduction in plants.

Further, most of what is known of gene transfer using traditional and 
rDNA techniques illustrates the profound manner in which they differ. 
Traditional crossing involves the movement of clusters of 
functionally linked genes, primarily between homologous chromosomes, 
and including the relevant promoters, regulatory sequences and 
associated genes involved in the coordinated expression of the 
character of interest in the plant. The molecular regulation of this 
process and the biochemical and evolutionary significance of these 
controls is poorly understood.

In contrast to traditional techniques, current rDNA technologies 
(those used in all currently approved rDNA crops) involve the random 
insertion of genes in the absence of normal promoter sequences and 
associated regulatory genes. As there are very few examples of plant 
traits in which we have identified the associated regulatory genes, 
the introduction of a fully 'functional' gene using rDNA techniques 
is currently not possible. R-DNA techniques also involve the 
simultaneous insertion of viral promoters and selectable markers and 
facilitates the introduction of genes from incompatible species. 
These genetic transformations cannot occur using traditional 
approaches - which further illustrates the profound manner in which 
these processes differ.

Genetic material can be moved within and between species by the 
poorly understood processes of gene transposition. Though the 
occurrence of this phenomenon in traditionally bred plants is 
superficially equivalent to rDNA techniques (which involve the random 
insertion of "artificial transposons"), the mechanisms governing this 
process and the significance of transposition in traditional gene 
transfer are unknown. Given our profound lack of understanding of 
these processes it is impossible to compare sensibly the two 
processes. Indeed, it can be argued that gene transfer via rDNA 
techniques resembles the process of viral infection far more closely 
than it resembles traditional breeding.

In summary, it is clear that gene transfer using rDNA techniques is 
substantially different from the processes that govern gene transfer 
in traditional breeding. The extent to which these processes differ 
will become increasingly clear as we gain a better understanding of 
the processes governing gene movement, expression and regulation.

The presumption of "Substantial Equivalence" - the basis for current 
regulatory principles - is profoundly flawed and scientifically 
insupportable.


Do rDNA Techniques offer Greater Precision?

One of the much-touted benefits of r-DNA techniques is the capability 
to introduce only a discrete and well-defined number of genes into 
the new cultivar whereas a traditional crossing event introduces 
thousands of genes. This ability to control the types and numbers of 
genes introduced speeds the introduction of a gene of interest by 
eliminating the need for extensive backcrossing to the elite parent. 
Many have suggested that this approach is fundamentally more 
"precise" than traditional breeding techniques and have argued that 
the technique is consequently "safer".

The ability to introduce a precisely defined compliment of genes 
using rDNA techniques, however, is not equivalent to the introduction 
of a precisely defined and biologically integrated character. Whereas 
the incorporation of a new character using traditional techniques 
occurs in a fully functional and appropriately regulated manner, rDNA 
gene introduction is more or less random, and does not involve 
introduction of the regulatory sequences normally associated with 
that gene. Traditional techniques, therefore, result in greater 
"biological precision" than random gene insertion using rDNA 
techniques.

The FDA policy statement further suggests that it is highly unlikely 
that rDNA techniques will result in the inadvertent production of 
allergens or toxic compounds and that once incorporated into the 
genome, the introduced gene functions like all other genes in the 
genome. These statements are offered in support of the premise that 
rDNA experiments are more predictable than traditional breeding 
approaches. This presumption is, however, clearly contradicted by a 
large volume of scientific literature and experimental experience 
that illustrates the propensity of rDNA techniques to produce 
unexpected and often lethal perturbations. Indeed metabolic and 
phenological perturbations are very frequently observed following 
transformation events and a high percentage of transformants show 
profound growth aberrations. Indeed the propensity of random gene 
introduction to cause metabolic disruption is well documented and 
actively used to probe gene function.

While extreme aberrations can be easily selected out, it is also 
highly likely that undetected biochemical perturbations remain 
following essentially all transformation events. Since it is not 
standard practice to screen transformants there is clearly a 
potential for biochemically abnormal transgenic plants to persist. 
This is further exacerbated through the use of tissue culture and 
embryo rescue etc. which can be used to "rescue" metabolically 
altered transgenic plants that might otherwise have been eliminated 
during early plant growth. Whether or not these same perturbations 
occur following traditional breeding is unknown. Lack of knowledge, 
however, is not proof of safety.

The metabolic perturbations caused by rDNA gene introduction may 
result in production of toxic compounds. Many plant species have the 
capacity to produce toxic compounds which, under natural conditions, 
serve to protect against animal and insect predation as well as 
contributing to disease resistance mechanisms. In certain species, 
such as those in the Solanum family, there are many well-
characterized and highly unpalatable or toxic compounds. It is very 
likely that the majority of the genes involved in the formation of 
these toxic and unpalatable compounds are still present (though not 
expressed) in modern tomato and potato. Given the random nature of 
rDNA gene insertion, and the use of a promiscuous viral promoter 
sequence, the potential clearly exists that tomato could be induced 
to produce a toxin as a result of an rDNA gene transfer. Whether this 
would occur with the same frequency following traditional sexual 
breeding is unknown. The presumption that it cannot occur is clearly 
invalid.

 Clearly the assumption that a transformed crop is exactly the sum of 
the original crop and the introduced gene is not acceptable. RDNA 
techniques are profoundly different from traditional breeding methods 
and are well known to cause unexpected metabolic perturbations. The 
principle of substantial equivalence is not scientifically 
justifiable; hence we can make no a priori assumption of the safety 
of any rDNA manipulation.


Do rDNA Techniques Provide an Acceptable Level of Risk?

The preceding discussion clearly demonstrates that the risks 
associated with rDNA technology cannot be determined given current 
understanding of gene expression. Nevertheless it has been argued 
that risk is a normal part of technological advancement and that 
acceptance of this risk is warranted in the instance of rDNA crops.

 While it is true that we accept risks as a normal part of life, most 
of the risks we accept are defined by experience and are understood 
before they are taken. Some risks are also taken because the rewards 
are perceived to outweigh the risks. Traditional breeding has on the 
whole been an acceptable risk with 10,000 years of experience, and a 
trust in the motives of those producing the new cultivars.

Many, however, are not yet prepared to accept the risks of rDNA 
technologies. This is in part due to a lack of understanding of the 
risks, the minimal benefit of the current crop of GMOs, and a 
mistrust of the motives of those selling the technology. Given the 
current state of our knowledge of this technology and the nature of 
the GMOs currently available, this lack of public trust is entirely 
reasonable. Public acceptance will require convincing demonstration 
of safety and the development of crops with a more direct benefit to 
the consumers.

The concerns expressed by many are further validated by the current 
generation of GMOs that have been incorporated into the food system 
without adequate public consultation and scientific scrutiny. The 
current generation of GMO crops do not provide any tangible public 
benefit, have not contributed to reduced food costs, and have no 
confirmed ecological benefit. This is well illustrated by the two 
most prevalent types of GMOs in use in the US.

Insect-resistant crops containing the gene encoding the Bacillus 
thuringiensis toxin have been planted widely in the US. This 
transgenic technique promises to reduce the use of pesticides and 
reduce growers' costs. While reduction in pesticide use is an 
admirable goal there are significant grounds to question the 
appropriateness of the current generation of Bt-producing crops and 
to question the haste with which these crops were released for 
widespread use.

The current generation of Bt crops utilize a single Bt gene rather 
than the complex of Bt genes that are available. There is widespread 
agreement amongst scientists that this use of a single Bt gene will 
increase the speed with which pest resistance will develop. To help 
alleviate the development of insect resistance the USDA and Monsanto 
now advise growers to plant refuge areas to ensure non-resistant 
insects persist under the premise that this will reduce the rate of 
resistance development. While this is theoretically sound there is 
insufficient ecological data to determine optimal size of these 
refuges or to estimate how effective they will be.

The current generation of Bt crops also utilize antibiotic resistance 
as the selectable marker and rely upon viral promoters to ensure high 
degrees of expression. This clearly introduces a risk associated with 
a promoter designed to be free of regulatory controls, it excites 
those who see viral and antibiotic-resistance genes as threatening, 
and it ensures that the Bt protein is distributed uniformly 
throughout the plant. The uniform presence of the Bt protein enhances 
the likelihood of resistance development and ensures that the protein 
is present throughout plant development and is present in the pollen. 
The death of Monarch larvae was a direct consequence of the presence 
of active Bt toxin in the pollen.

While some have questioned the scientific relevance of this study it 
did illustrate the inherent flaws in this cultivar.

Methods exist (or will soon exist) that make the use of viral 
promoters and antibiotic resistance markers unnecessary. There is no 
justification for the expression of Bt in the pollen, and the release 
of cultivars with a single Bt gene is certain to hasten resistance 
development. In the absence of data to support the refugia concept 
there is very little to prevent the development of widespread insect 
tolerance of Bt.

Clearly the release of the first generation of Bt-containing crops 
was premature and based upon flawed scientific principles. Regulatory 
and scientific support for this cultivar is clearly questionable.

The other dominant type of GMO in use today is the Roundup-Ready 
varieties of cotton, soybean and corn. Not only do these cultivars 
contain many of the same questionable genes as those in Bt crops, but 
also they have the additional propensity to contribute to the 
development of herbicide-resistant weed species for which the 
consequences are poorly understood. Roundup-Ready crops are also of 
questionable ecological value and build a long-term dependence on the 
use of the herbicide Glyphosate.

Not insignificantly, the overtly 'corporate' nature of these crops 
and the dependence they build on high cost and ecologically 
questionable technologies has resulted in widespread suspicion of the 
motives of those promoting these cultivars.

It is abundantly clear that the current generation of GMOs were 
developed using an untested and unsophisticated technology and were 
released prematurely to ensure early returns on corporate investment. 
Clearly this does not represent a sound justification for the release 
and widespread use of these crops.

Perhaps one of the most profoundly flawed justifications of GMOs is 
illustrated in the often-cited refrain "GMO foods have been widely 
available in the marketplace for the past 5 years and not one 
incident of harm to public health has been documented". Since every 
introduced gene is inserted into a different genetic location, and 
every gene differs in functions and interactions within the genome, 
and as every species can be expected to 'react' differently to the 
gene introduction process, it is clear that the safety of one GMO is 
in no way predictive of the safety of another. In many respects the 
claim of safety by association is no more valid than the claim that 
the safety of aspirin predicts the safety of all future drugs.


Conclusion

The real threat to the future of plant biotechnology is the 
irresponsible and premature releases of the first generation of GMOs 
that are full of unsound scientific assumptions, rife with careless 
science, and arrogantly dismissive of valid concerns. The current 
generation of GMOs provide little real benefit except corporate 
profit and marginally improved grower returns, while at the same time 
introducing a host of poorly studied human and ecological risks. Not 
surprisingly, many have questioned the value of these crops and the 
integrity of those who support their use.

Given these issues and the overall lack of knowledge of rDNA 
technology it can only be concluded that the current FDA regulations 
guiding the release and testing of GMOs is inadequate. It can further 
be concluded that the technology is inadequately developed to ensure 
its safety. In the absence of a sound scientific basis to predict the 
full consequences of rDNA crop development, we must either subject 
all new crops to a rigorous testing program that considers all 
potential health, social and environmental concerns or halt further 
release of rDNA crops until a firm scientific understanding of the 
biological principles is attained.

As scientists it is our responsibility to recognize that we do not 
yet have sufficient knowledge of the process to use it safely. We 
must work towards addressing all of the concerns explicit in the 
current generation of crops, and must support a rigorous testing 
program to ensure the safety of all GMO foodstuffs in the interim. To 
date many in the scientific community have been unwilling to 
rationally consider the concerns surrounding the current GMOs and 
have wrongly considered that a defence of GMOs is a prerequisite to 
protect the science of plant biotechnology. Nothing could be further 
from the truth or more threatening to the future of this technology.

                              *****

To find out more about how the FDA in the US has blatantly ignored 
the advice of its own scientists in assessing such risks see:
www.biointegrity.org






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