A Very Scary Scientific Article About a Viral Promoter,
CaMv, Found in Most Genetically Engineered Foods

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>From List: Biotech Activists (biotech_activists@iatp.org)
>
Date Posted: 12/14/1999
Posted by: M.W.Ho@open.ac.uk
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The CaMV Promoter Story
The Cauliflower Mosaic Viral Promoter - A Recipe for Disaster?
by Dr. Mae-Won Ho, author of the book Biotechnology:Dream or Nightmare?

The story of CaMV promoter encapsulates and draws attention to the hazardous
nature of the genetic engineering process itself as well as the foreign gene
constructs created and released into the environment.
Contrary to our usual practice, we are reviewing this publication before it
is actually in print because of the overwhelming number of attacks on it
which have already appeared on the net, and because we have been asked to
provide an accessible account of this somewhat technical article. Our
official rebuttal has been circulated earlier. In case you have missed it
please visit our ISIS website. <http://www.i-sis.dircon.co.uk>

Prof. Joe Cummins of the University of Western Ontario was the first
scientist to question the safety of the cauliflower mosaic viral (CaMV)
promoter, which is in practically all GM crops currently grown commercially
or undergoing field trials. His initial concern was that the promoter could
recombine with other viruses to generate new disease-causing viruses. In our
paper, we review some recent findings which give further grounds for
concern, and have recommended the immediate withdrawal of all crops and
products containing the CaMV promoter.
Ref.: Ho, M.W., Ryan, A. and Cummins, J. (1999). The cauliflower mosaic
viral promoter - a recipe for disaster? Microbial Ecology in Health and
Disease (in press).

To begin with, a 'promoter' is a stretch of genetic material that acts as a
switch for turning genes on. Every gene needs a promoter in order to work,
or to become expressed. But the promoter is not a simple switch like that
for an electric light, for example, which has only two positions, either
fully on or fully off. Instead, the promoter has many different modules that
act as sensors and to enable it to respond, in ways we do not yet fully
understand, to different signals from other genes and from the environment,
which tell it when and where to switch on, by how much and for how long. And
under certain circumstances, the promoter may be silenced, so that it is off
all the time.

All in all, the role of the promoter of a normal gene in an organism is to
enable the gene to work appropriately in the extremely complex regulatory
circuits of the organism as a whole. The promoter associated with each of
the organism's own genes is adapted to its gene while the totality of all
the genes of the organism have been adapted to stay and work together for
millions, if not hundreds of millions of years. The genome of each organism
is organised in a certain way which is more or less constant across the
species so individuals within a species can freely interbreed. Each species
protects its integrity and remains genetically stable because there are
biological barriers that prevent distant species from interbreeding or
otherwise exchanging genetic material. Foreign DNA are generally broken down
or inactivated.

Genetic engineering attempts to break down these biological
barriers so genes can be arbitrarily transferred between species that would
never interbreed in nature. In order to do so, special tricks are needed.
When genetic engineers transfer foreign genes into an organism to make a
GMO, they also have to put a promoter in front of each of the genes
transferred, otherwise it would not work. The promoter plus the gene it
switches on constitutes a 'gene-expression cassette'. Many of the genes are
from bacteria and viruses, and the most commonly used promoter is from the
caulifower mosaic virus. Several gene-expression cassettes are usually
stacked, or linked in series, one or more of them will be genes that code
for antibiotic resistance, which will enable those cells that have taken up
the foreign genes to be selected with antibiotics. The stacked cassettes are
then spliced in turn into an artificial gene carrier or 'vector'. The vector
is generally made by joining together parts of viruses and other infectious
genetic parasites (plasmids and transposons) that cause diseases or spread
antibiotic and drug resistance genes.

In the case of plants, the most widely
used vector is the 'T-DNA' which is part of the tumour-inducing plasmid
('Ti plasmid') of Agrobacterium, a soil bacterium that infects plants and
give rise to plant tumours or galls. The role of the vector is to smuggle
genes into cells that would otherwise exclude them. And more importantly,
the vector can jump into the cell's genome and so enable the gene-expression
cassettes it carries to become incorporated into the genetic material of the
cell. The genetic engineer cannot control where and in what form the vector
jumps into the genetic material of the cell, however. And this is where the
first unpredictable effects can arise. Each transgenic line is unique, and
gives rise to different unintended effects, and in the case of food, can
include unexpected toxins and allergens.

The foreign genetic material transferred to make a transgenic organism -
referred to as the 'transgenic DNA' or the 'construct' - is quite
complicated. It consists of new genes and new combinations of genes - from
diverse species and their genetic parasites - which have never existed in
nature. Such chimaeric constructs are already known to be structurally
unstable, that is, they are prone to make and break and rearrange. It is to
be expected that such structural instability can only increase when the
construct is introduced, by a totally hit or miss process, into a new
genome. Transgenic instability is a well-known problem for the industry.
Transgenic lines often do not breed true (see Srivastava et al, 1999, in
item #3 below).

Why use a promoter from a virus such as the CaMV? A virus is a genetic
parasite that has the capability to infect the cell and hi-jack the cell to
make many copies of itself in a short period of time. Its promoter is
therefore very aggressive and hence popular with genetic engineers, as it
effectively makes the gene placed next to it turn on full blast, at perhaps
a thousand times the volume of any of the organism's own gene. Having it in
the genome is rather like having the loudest phrase of a heavy-metal piece
played with the most powerful amplifier simultaneously over and over again
throughout a live performance of a Mozart concerto. What the CaMVpromoter
actually does is to place the foreign gene outside the normal regulatory
circuits of the host organism, subjecting the host organism effectively to a
permanent metabolic stress. This will multiply the unintended, unpredictable
effects, which are legion in transgenic organisms. It may also be another
reason why transgenic lines are notoriously unstable (Finnegan, J. &
McElroy, D. 1994, Bio/Technology 12, 883). The organism generally reacts to
the presence of foreign genetic material by breaking it down or inactivating
it. Even after the genetic material is incorporated into the genome, it can
silence the foreign genes so that they are no longer expressed (see Item #3
below).

The key recent finding, which provoked our review, was the report (Kohli et
al, (1999) The Plant Journal 17, 591) that the CaMV promoter contains a
'recombination hotspot' - a site where the DNA tends to break and join up
with other DNA, thus changing the combination and arrangement of genes.
Around the hotspot are several short stretches or modules for binding
various enzymes, all of which are also involved in recombination , ie,
breaking and joining DNA. Furthermore, the CaMV promoter recombination
hotspot bears a strong resemblance to the borders of the T-DNA vector
carrying the transgenes, which are also known to be prone to recombination.
It is that which enables the vector to invade the cell's genome in the first
place.

The aim of our original paper, restated explicitly in our official rebuttal,
was to review the relevant findings and, in particular, to point out the
implications, which the researchers themselves are unwilling or unable to
draw. The findings that transgenic DNA has the tendency to break and join in
several places imply that parts or all of it may be more likely than the
plant's own DNA to jump out of the genome and successfully transfer
horizontally to unrelated species. Horizontal gene transfer, in this
context, means the transfer of the genetic material directly by infection to
the genetic material of unrelated species, in principle to all species
interacting with the GMO: bacteria, fungi, earthworms, nematodes, protozoa,
insects, small mammals and human beings. This process is uncontrollable and
cannot be recalled. The damages done are hence irreversible. Transgenic DNA
has been designed to be invasive and to overcome species barriers; once
released, it will invade different organisms, especially bacteria which are
in all environments, where it will multiply, mutate and recombine.
There are additional findings which suggest an increased potential for the
horizontal spread of transgenic DNA. For example, enzymes that insert the
transgenic DNA into the genome can also help them to jump out again; DNA
released from both dead or live cells can survive without being degraded in
all environments, including the mouth and gut of mammals; DNA can be
readily taken up into cells; and all cells can take up naked or free DNA.
The instability of transgenic DNA may also be enhanced as the result of the
metabolic stress inflicted on the organism by the CaMVpromoter that gives
continuous over-expression of transgenes.

The major consequences of the horizontal transfer of transgenic DNA are the
spread of antibiotic resistance marker genes among bacteria and the
generation of new bacteria and new viruses that cause diseases from the many
bacterial and viral genes used. The generation of new viruses could occur by
recombination with live or dormant viruses that we now know to be present in
all genomes, plants and animals included. Recombination with defective,
dormant animal viral promoters may also occur, as we know that there are
modules within the promoter that are interchangeable between plant and
animal promoters. Recombination of CaMV promoter modules with defective
promoters of animal viruses may result in recombinant promoters that are
active in animal cells, causing over-expression of one or the other of
dozens of cellular genes which are now believed to be associated with
cancer.

There is sufficient scientific evidence to support well-founded suspicion of
serious, irreversible harm to justify the immediate withdrawal of all GM
crops and products containing the CaMV promoter from environmental release.
(M.W.H.)

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