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[SANET-MG] death domains



http://www.i-sis.org.uk/DeathDomains.phpISIS Press Release 21/02/05
Death Domains in New Bio-pesticides
Professor Joe Cummins warns of new bio-pesticides the US Food and Drug
Administration proposes to deregulate that may cause all animal cells to
commit suicide


Programmed cell death universal in multi-cellular organisms
Cell death is an important feature of growth and differentiation in all
multi - cellular organisms. In 1972, the term “apoptosis” was used to
describe the cell changes associated with programmed cell suicide. The
death programme includes blebs appearing on the cell membrane, shrinkage
of the cell, characteristic patterns of DNA fragmentation and finally
disassembly of the cell. Each cell is equipped with regulatory proteins
bearing “death domains”. There is a common design to the death domains
and their regulatory circuitry in animals and plants. The research on
programmed cell death and anti-death signaling has grown very large and
its implication in cancer care, immunity and even pest control are being
explored. Numerous reviews of the subject have been written [1-3].

The Bacillus thuringiensis (Bt) toxin genes currently employed in
commercial crops are all members of a class of toxin proteins that
accumulate, as crystals, in stationary stage bacteria (bacteria that
have completed their growth cycle) these genes are designated Cry
followed by numbers and letters that indicate there origin and
specificity. These toxins all create pores in the insect cell membranes
leading to osmotic lysis of the cells, or cells bursting as they fill up
with water.

Another kind of Bt toxin, the VIP (vegetative insecticidal protein)
group of toxins are produced in vegetative cells, the genes are
designated VIP followed by numbers and letters related to their origin
and specificity. US Patents 6,291,156 [4] and 6,429,360 [5] from
Syngenta Corporation provided compelling evidence that VIP3A toxin
contained putative death domains and that the toxin induced apoptosis in
insect cells.

The “death domain” is a 60 to 70 amino acid long motif, which is
involved in protein to protein interaction, and is shared by proteins
with diverse cellular functions. Some of the protein members containing
death domain motifs include receptors known to be associated with
apoptotic processes, such as the Fas receptor and the tumour necrosis
factor (TNF) in mammalian cells (references provided in the patent). The
patent admits that, “the death core pathway seems to be phylogenetically
conserved”, while “the signal transduction pathway from the receptor to
the death core pathway is subject to variation across organisms.”

Earlier reports from the United States Department of Agriculture (USDA)
laboratory in Beltsville, Maryland showed that crude preparations of
mixed Bt toxins induced apoptosis in insect larvae. Agents that induce
apoptosis may provide powerful pest control, but their impacts on
non-target animals and plants need to be carefully evaluated [8] in view
of the evidence that the core pathway is conserved in evolution while
the signal transduction pathway is subject to variation.

A research group from Syngenta published a study showing that along with
apoptosis, VIP3A supported pore formation in the membrane. The research
report noted that the pore formation mechanism was not mutually
exclusive with apoptosis; but the researchers believed that pore
formation was the main basis for toxicity [9].

In 2005, Syngenta petitioned for non-regulated status of cotton event
COT102, a cotton variety resistant to Lepidopteran pests because it was
modified with a synthetic approximation of the VIP3A(a) gene [10]. The
USDA/APHIS Environmental Assessment of transgenic cotton event COT102
accompanied the petition [11]. Surprisingly both the petition and the
environment assessment appear to have ignored the aspect of apoptosis
and death domains in their extensive reviews. Even though USDA
researchers had determined that crude Bt toxin preparation induced
apoptosis, the formal reviews and petition appear to have completely sid
e-s tepped the implications of death domains and apoptosis for
non-target animals and plants.

The company submission was posted as a docket for public consultation at
http://docket.epa.gov/edkfed/index.jsp

04-51-1 APHIS-2005-0007 Syngenta Seeds, Inc.; Availability of Petition
and Environmental Assessment for Determination of Nonregulated Status
for Cotton Genetically Engineered for Insect Resistance 01-28-2005
General Docket Notice 03-29
04-51-2 Syngenta Petition 03-155-01p for Determination of Nonregulated
Status for Lepidopteran Resistant Event COT102

Comments have to be submitted prior to the closing date, 29 March 2005.
The main question is: “have adequate safety tests been done to allow
exposure to the toxin and its gene in fiber, food and feed?”

It is not at all clear that the studies have been adequate.

References
Bhardwa A. and Aggarwa B. Receptor-mediated choreography of life and
death Journal of Clinical immunology 2003, 23, 317-32.
Nam J, Mani K, Ashton A, Peng C, Krishnamurthy B, Hayakawa Y, Lee P,
Korsmeyer S and Kitsis R. Inhibition of both the extrinsic and intrinsic
death pathways through nonhomotypic death-fold interaction Molecular
Cell 2004, 15,901-12.
Barnhart B, Lee J, Alappat E.and Peter M. The death effector domain
protein family Oncogene 2003, 22, 8634-44
Estruch J. and Yu C. Plant Pest Control 2001 US Patent 6,291,156.
Estruch J, Warren G, Desai N, Kozeil M, and Nye G. Plant Pest
Control.2001 US Patent 6,429,360.
Loeb M, Martin P, Narang, N, Hakim, R, Goto S. and Takeda, M. Control of
life, death, and differentiation in cultured midgut cells of the
lepidopteran, Heliothis virescens . In Vitro Cell Dev Biol Anim . 2001,
37,348-52
Loeb M, Hakim R, Martin P,Narang N, Goto S and Takeda M. Apoptosis in
cultured midgut cells from Heliothis virescens larvae exposed to various
conditions. Archives of Insect Biochemistry and Physiology 2000, 45:12–23.#
Cummins J. New GM toxin looms over our food 2003
http://www.i-sis.org.uk/full/NGMTLOOFFull.php ISIS Press Release 02/12/03
Lee M, Walters F, Hart H, Palekar N and Chen J. The mode of action of
the Bacillus thuringiensis vegetative insecticidal protein Vip3A differs
from that of Cry1Ab endotoxin. Applied and Environmental Microbiology
2003, 69,4648-57.
Artim L. Application for determination of non-regulated status for
lepidopteran insect protected VIP3A cotton transformation event COT102
2005 http://www.aphis.usda.gov/brs/aphisdocs/03_15501p.pdf
USDA/APHIS Environment Assessment Syngenta Petition 03-155-01p for
determination of noinregulated status for lepidopteran resistant event
COT102 2005 http://www.aphis.usda.gov/brs/aphisdocs/03_15501p.pdf

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