Science in Society Archive

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

04-51-1APHIS-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
04-51-2Syngenta 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.

Article first published 21/02/05



References

  1. Bhardwa A. and Aggarwa B. Receptor-mediated choreography of life and death Journal of Clinical immunology 2003, 23, 317-32.
  2. 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.
  3. Barnhart B, Lee J, Alappat E.and Peter M. The death effector domain protein family Oncogene 2003, 22, 8634-44
  4. Estruch J. and Yu C. Plant Pest Control 2001 US Patent 6,291,156.
  5. Estruch J, Warren G, Desai N, Kozeil M, and Nye G. Plant Pest Control.2001 US Patent 6,429,360.
  6. 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
  7. 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.#
  8. Cummins J. New GM toxin looms over our food 2003 http://www.i-sis.org.uk/NGMTLOOF.php I-SIS Press Release 02/12/03
  9. 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.
  10. 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
  11. 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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