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	Attached is a PDF from the 
gene-jiggerers' highest-status journal.  This 
one-page letter is a very handy item to send to 
any scientist who hasn't yet worked out what to 
think about gene-tampering.  It is of first 
importance, not least for the briefest true 
summary of the lethal GM-tryptophan.
	The status of the journal Nat Biotech in 
the whole of science is not actually high, but 
within the gene-tamperers' sheltered workshop it 
has top status.
	The status of Prof Schubert is genuinely 
high.  He used to lunch with Crick often.

	The Schubert Letter is reproduced as txt 
below for those not equipped with the free 
Acrobat Reader to read PDFs.

RM

=====




	A different perspective on GM food

				David Schubert

Nature Biotechnology  vol. 20   p. 969
  Oct 2002

  As a cell biologist, I am very discouraged by 
the nature of the ongoing "debate" on the 
introduction of genetically modified (GM) plants 
into the marketplace.  This discussion has 
usually pitted irrational emotional arguments 
against the apparently rational notion that 
genetic engineering is just like traditional 
plant breeding, only more specific.  In 
particular, I believe that insufficient attention 
has been paid to three important issues:first, 
introduction of the same gene into two different 
types of cells can produce two very distinct 
protein molecules;  second, the introduction of 
any gene, whether from a different or the same 
species, usually significantly changes overall 
gene expression and therefore the phenotype of 
the recipient cell; and third, enzymatic pathways 
introduced to synthesize small molecules, such as 
vitamins, could interact with endogenous pathways 
to produce novel molecules.  The potential 
consequence of all of these perturbations could 
be the biosynthesis of molecules that are toxic, 
allergenic, or carcinogenic.  And there is no a 
priori way of predicting the outcome.  In what 
follows I outline these concerns and argue that 
GM food is not a safe option, given our current 
lack of understanding of the
consequences of recombinant technology.

The biological activity of a protein can be 
modified by gene splicing, which alters the 
primary amino acid sequence, and by the 
post-translational attachment of such moieties as 
phosphate, sulfate, sugars, or lipids.  The 
nature of these modifications is markedly 
dependent upon the cell type in which the protein 
is expressed.  For example, if the P-amyloid 
precursor protein, which is involved in 
Alzheimer's disease, is expressed in glial cells, 
it contains covalently attached chondroitin 
sulfate; but when it is expressed in brain nerve 
cells the protein contains a much simpler sugar 
(1).   This is because each cell type expresses a 
unique repertoire of enzymes capable of modifying 
protein structure by mRNA splicing or at the
post-translational level.  In the case of the 
P-amyloid precursor protein, its adhesive 
properties are altered by the attachment of 
different carbohydrates (2).  With our current 
state of knowledge, however, there is no way of 
predicting either the modifications or their 
biological effects.   Therefore, a toxin that is 
harmless to humans when made in bacteria could be 
modified by plant cells in many ways, some of 
which might be harmful.

My second concern is the potential for the 
introduction of a foreign gene to either evoke 
the synthesis of toxic, carcinogenic, 
teratogenic, or allergenic compounds, or 
downregulate the synthesis of a beneficial plant 
molecule.  Introduction of one gene usually 
alters the gene expression pattern of the whole 
cell, and typically each cell type of the 
organism will respond differently.  One example 
involves the transfection of a receptor gene into 
human cells.  In this case, the protein was a 
closely related isoform of an endogenously 
expressed gene (3).  Monitoring the pattern of 
gene expression using microarray technology 
showed that mRNA levels for 5% of the genes were 
significantly upregulated or downregulated. 
Recent studies in transgenic plants showed that 
the over-expression of a gene involved in pectin 
synthesis had no effect in tobacco, but caused 
major structural changes and premature leaf 
shedding in apple trees (4).  Although these 
sorts of unpredicted changes in gene expression 
and function are frequently
observed, they have received very little 
attention.  Furthermore, they are not unexpected. 
The maintenance of a specific cell phenotype 
involves a very precise balancing act of gene 
regulation, and any perturbation might be 
expected to change the overall patterns of gene 
expression.  The problem, as with secondary 
modifications, is that there is currently no way 
to predict the resultant changes in protein 
synthesis.

Third, the introduction of genes for all or part 
of a new enzymatic pathway into plants could lead 
to the synthesis of unexpected or even totally 
novel products through an interaction with 
endogenous pathways.  Some of these products 
could be toxic.  For example, retinoic acid 
(vitamin A) and its derivatives are used in many 
signaling events that control mammalian 
development (5).  As these compounds have effects 
at ultra-low concentrations, a GM plant making 
vitamin A might also produce retinoic add 
derivatives, which act as agonists or antagonists 
in these pathways, resulting in direct toxicity 
or abnormal embryonic development.  A relevant 
example is a genetic manipulation carried out in 
bacteria during the 1980s to increase the yield 
of tryptophan for use as a nutritional 
supplement.  The resultant product caused a novel 
illness that was highly correlated with the 
aberrant appearance of specific trace 
contaminants (6).

Given that GM plants will sometimes produce 
different amounts of proteins, and perhaps 
totally new proteins, as compared with the 
parental species, what are the possible results? 
A worst-case scenario would be that an introduced 
bacterial toxin is modified to make it toxic to 
humans.  Prompt toxicity might be rapidly 
detected once the product entered the marketplace 
if it caused a unique disease, and if the food 
were labeled for traceability, as were the GM 
batches of tryptophan.  However, cancer or other
common diseases with delayed onset would take 
decades to detect, and might never be traced to 
their cause.  Conversely, plant flavonoids and 
related molecules have great health benefits (7), 
and there is evidence that these can be depleted 
in GM crops (8).

If the above concerns are valid, what can be done 
to address them?  Secondary modifications could 
be assayed by monitoring of the introduced gene 
product by mass spectroscopy; changes in gene 
expression could be assayed by DNA chips; and 
metabolically active molecules could be measured 
biochemically.
The problem is, of course, that unless we know 
exactly what to look for, we are likely to miss 
the relevant changes.  To me, the only reasonable 
solution is to require that all GM plant products 
destined for human consumption be tested for 
long-term toxicity and carcinogenicity before 
being brought to
market.  These safety criteria must be met for 
many chemicals and all drugs, and the magnitude 
of harm caused by a widely consumed toxic food 
could well be much greater than that from any 
single drug.  However, even extensive animal 
testing might not detect the consequences of 
deficiencies in beneficial plant products.  As GM 
crops offer potential benefits, it would be in 
the industry's best interest to more thoroughly 
examine these products before continuing with 
their introduction into the food supply.

1. Shioi, J. et al.  J. Biol. Chem. 270,11839-11844 (1995).
2. Salinero, 0.. Moreno-Flores, M.T. & Wandosell, F.  J. Neurosci. Res. 60,
     87-97 (2000).
3. Srivastava, M., Eidelman, 0. & Pollard, H.B.  Mol. Med. 5, 753-767 (1999).
4. Atkinson, R.G., Schroder, R., Hallett, I.C., Cohen, D. & MacRae, E.A.
      Plant Physiol. 129, 122-133 (2002).
5. Gronemeyer, H. & Miturski. R.  Cell Mol. Biol. Lett. 6, 3-52 (2001).
6. Kilbourne, E.M., Philen, R.M., Kamb, M.L. & Falk, H.  J. Rheumatol. Suppl.
     46,81-88 (1996).
7. Middleton, E., Kandaswami, C. & Theoharides, T.C.  Pharmacol. Rev. 52,
     673-751 (2000).
8. Lappé, M.A., Bailey, E.B., Childress, C. & Setchell, K.D.R. J. Med. Food
     1, 241-245 (1999).

David Schubert is a professor at the Sulk Institute, 10010 N. Torrey Pines
Road, La Jolla, CA 92037 ([log in to unmask])

www.nature.com/naturebiotechnology

-----
The main response in Nat Biotech to the Schubert 
Letter was the 'enraged' rave (Nov 2002) by main 
Monsanto-connected gene-jockeys Roger Beachy, 
Wayne Parrott et bulk:-
	 
	' The reality is that "unintentional 
consequences" are much more likely to occur in 
nature than in biotechnology because nature 
relies on the unintentional consequences of blind 
random genetic mutation and rearrangement to 
produce adaptive phenotypic results, whereas GM 
technology employs precise, specific, and 
rationally designed genetic modification toward a 
specific engineering goal. '

	I commend this sentence as a prototypical 
example of stupid reductionism, bad science, and 
the type of blunder depicted in Genesis 3.
	Indeed I claim that this immortal 
sentence shows how the big lie entailed in 
atheism is all to likely to cause drastic 
degradation of truth & reason.

-- 
L. R. B. Mann  M.Sc  Ph.D
applied ecology
22a Ardern Ave., Stanmore Bay 0932, New Zealand
(9) 424 0808
http://www.kuratrading.com/HTMLArticles/writings.htm