Science in Society Archive

Transgenic Plum Gets USDA Non-regulated Status Based on False Claims of Safety

Prof. Joe Cummins and Dr. Mae-Wan Ho rebut USDA conclusion that transgenic DNA and RNA are non-toxic

USDA deregulates its own transgenic plum despite overwhelming public objection

The United States Department of Agriculture Animal and Plant Health Inspection Service (USDA/APHIS) has recently granted non-regulatory status to a transgenic plum resistant to plum poxvirus [1] after receiving 1 725 comments from state farm bureaus, organic growers, growers associations, consumer groups, agriculture support industries, academic professionals and individuals, with respondents against the petition (1 708) outnumbering those in favour (17) by a factor of 100 to 1.

APHIS was clearly biased in favour of the petition in their Environmental Assessment, and attempted to justify its decision by stating: “The majority of academic researchers, as well as the state farm bureaus that submitted comments, support granting non-regulated status to the C5 plum. The majority of those who submitted comments opposing granting non-regulated status were submitted by organic grower or consumer groups, organic growers, those who favour organic agriculture or those who are opposed to genetic engineering technology in general.”

Deregulation based on obsolete and irrelevant FDA notice

APHIS maintains that, in general RNA and DNA have no toxic properties [1] based primarily on a Food and Drug Administration (FDA) 1992 GRAS notice on transgenic microbes used to produce animal proteins under contained conditions, which is irrelevant and highly misleading when applied to environmental release in the case of the C5 transgenic plum. More importantly, the FDA notice is obsolete in view of numerous scientific findings made since, and its recommendations should be rejected forthwith. For example, the extensive regulatory role of small RNA molecules, similar to those in the virus resistance of C5 plums, was not mentioned in the FDA notice, as it had not yet been discovered; nor indeed, the potentially fatal effects of such RNA molecules in mammals highlighted in our detailed comment to the USDA [2] (USDA Proposes to Deregulate Its Own Transgenic Plum, SiS 31).

Despite the fact that a small RNA molecule was present in high concentrations in the transgenic plum, APHIS maintains that: “Nucleic acids (i.e., RNA and DNA) are present in all living organisms and are not known to have any toxic properties. Nucleic acids are considered to be “generally recognized as safe” (GRAS) by the U.S. Food and Drug Administration (FDA) (FDA 1992) and exempt from the requirement of a tolerance under the Federal Food Drug and Cosmetic Act by the U.S. Environmental.”

APHIS dismissed comments questioning the safety of the small RNAs responsible for providing resistance in C5 plum, including one comment from us [2] pointing to the use of small RNAs in RNA interference (RNAi) gene therapy and its potential adverse health effects. APHIS insists that, “the safety of nucleic acids is widely accepted”, as both RNA and DNA are part of all food products that we consume; further, “given that plant viruses infect a tremendous amount of the fruits and vegetables that we consume, it is highly likely that humans have been exposed to the same or similar viral RNA that may be expressed in a coat-protein expressing plant.” As to the concern about safety arising from findings in RNAi gene therapy, APHIS states that such RNAs “would be specifically designed and intended for targeted use in humans, and they would be significantly different than those found in the C5 plum.”

All of the APHIS statements cited are false and or misleading, and are contradicted by extensive scientific literature.

Small RNAs are potentially lethal to mammals

It is questionable whether people tend to eat virus-infected fruits and vegetables; also, potentially toxic small RNA molecules are produced, not by the virus but by the transgenic plum as the result of the insertion of viral DNA into the plum genome. Virus infected non-transgenic plums would not make large quantities of the small RNA that prevents virus replication.

There is substantial evidence that the small RNA molecules may be toxic to animal cells (see below), and produce off target effects in plants. Contrary to the statement made by APHIS (above) suggesting that specific sequences were designed for gene therapy, the researchers tested many different RNA sequences for toxicity to mice. Out of 49 sequences tested, the majority (36) were severely toxic, 23 were lethal in every case, killing the animals within two months [3] (Gene Therapy Nightmare for Mice, SiS 31). The fact is, the small RNA molecules produced in the transgenic plum have never been tested for their toxicity in animals and they have not previously been produced in quantities in non-transgenic plums or any other crop plants. The potential toxicity of small RNAs is featured in a number of publications between 2004 and 2006 [4-9], which show that APHIS’ conclusion that RNA molecules are safe for humans is false and invalid.

Toxic DNA a fact of life

APHIS further maintains that DNA molecules are intrinsically non-toxic based on the 1992 FDA GRAS notice [1]. Even though toxic DNA is not a major issue in the transgenic plum, it is worth pointing out that the toxicity of certain DNA molecules is well established [10-12]. DNA molecules are recognized by the immune system as a means of activating defence against pathogenic bacteria and viruses. A strong immune reaction is triggered; even one leading to death in mammals, as stated in a report published in 2004 [13]:

“The mammalian innate immune system has the ability to recognise and direct a response against incoming foreign DNA. The primary signal that triggers this response is unmethylated CpG motifs present in the DNA sequence of various disease-causing pathogens. These motifs are rare in vertebrate DNA, but abundant in bacterial and some viral DNAs. Because gene therapy generally involves the delivery of DNA from either plasmids of bacterial origin or recombinant viruses, an acute inflammatory response of variable severity inevitably results. The response is most serious for non-viral gene delivery vectors composed of cationic lipid-DNA complexes, producing adverse effects at lower doses and lethality at higher doses of complex.”

APHIS’ conclusion on the lack of toxicity of DNA is evidently also false and misleading.

We have stated on many occasions (most recently in GM Food Nightmare Unfolding in the Regulatory Sham  [14], I-SIS scientific publication) that transgenic DNAs, as opposed to non-transgenic DNA, share certain features that make them potentially unsafe.

  • Sequence homologies to many species including pathogenic bacteria and viruses, which enhances horizontal gene transfer and recombination to create new pathogens
  • Antibiotic resistance marker genes that could transfer horizontally to pathogenic bacteria and render infections untreatable
  • Recombination/fragmentation hotspots such as the CaMV 35S promoter that further enhance horizontal gene transfer and recombination
  • Insertion sequences that enable transgenic DNAs to invade genomes and transfer horizontally
  • Strong viral promoters that could activate oncogenes and trigger cancer.

A string of false and invalid claims on safety

In conclusion, APHIS has falsely claimed that RNA and DNA molecules are intrinsically safe for humans, based solely on an obsolete FDA notice now refuted by numerous observations.

This is the latest in a long string of false and invalid claims on safety from the USDA.  I-SIS has submitted at least 34 detailed objections containing safety warnings against deregulation or field releases of genetically modified organisms (GMOs) to the USDA and other US regulatory agencies since 2001 [15], all to no avail. The same goes for ISIS’ submissions to the European Food Safety Authority and the UK Food Safety Authority [14].

However, the US judiciary system appears to be catching up with USDA’s cavalier attitude towards environmental safety assessment [16] (Approval of GM Crops Illegal, US Federal Courts Rule , SiS 34), and has imposed the first ban on a GM crop (alfalfa) in the country. The US has joined the avalanche of bans and moratoriums hitting GM crops around the world over the past year as policy makers are waking up to the irrefutable mass of evidence piling up on the hazards inherent to GMOs [14, 17, 18] (No to GMOs, No to GM Science, SiS 35; GM Science Exposed: Hazards Ignored, Fraud, Regulatory Sham, and Violation of Farmers' Rights. ISIS CD book).

References

  1. Approval of USDA-ARS Request (04-264-01P) Seeking a Determination of Non-regulated Status for C5 Plum Resistant to Plum Pox Virus, Finding of No Significant Impact and Decision Notice. Federal Register 72, No. 134 / Friday, July 13, 2007 / Notices.
  2. Cummins J. and Ho MW. USDA proposes to deregulate its own transgenic plum. Science in Society 31,  5-7, 2006.
  3. Ho MW. Gene therapy nightmare for mice could human be next? Science in Society 31, 25, 2006.  
  4. Grimm D, Streetz KL, Jopling CL, Storm TA, Pandey K, Davis CR, Marion P, Salazar F, Kay MA. Fatality in mice due to oversaturation of cellular microRNA/short hairpin RNA pathways. Nature 2006, 441(7092), 537-41.
  5. Marsden,P. RNA interference as potential therapy — not so fast.  N Engl J Med 2006, 355, 953-4.
  6. Barik S. RNAi in moderation. Nat Biotechnol. 2006, 24(7), 796-7.
  7. Snove O Jr, Rossi JJ.    Toxicity in mice expressing short hairpin RNAs gives new insight into RNAi. Genome Biol. 2006, 7(8), 231.
  8. Fish RJ, Kruithof EK. Short-term cytotoxic effects and long-term instability of RNAi delivered using lentiviral vectors. BMC Mol Biol. 2004, 5(9),1-15
  9. Jackson AL, Burchard J, Schelter J, Chau BN, Cleary M, Lim L, Linsley PS.    Widespread siRNA 'off-target' transcript silencing mediated by seed region sequence complementarity. RNA 2006, 12(7), 1179-87.
  10. Luyer MD, Buurman WA, Hadfoune M, Wolfs T, van't Veer C, Jacobs JA, Dejong CH, Greve JW. Exposure to bacterial DNA before hemorrhagic shock strongly aggravates systemic inflammation and gut barrier loss via an IFN-gamma-dependent route. Ann Surg. 2007, 245(5), 795-802.
  11. Obermeier F, Dunger N, Deml L, Herfarth H, Schölmerich J, Falk W. CpG motifs of bacterial DNA exacerbate colitis of dextran sulfate sodium-treated mice. Eur J Immunol. 2002, 32(7), 2084-92
  12. Khazanov E, Simberg D, Barenholz Y.  Lipoplexes prepared from cationic liposomes and mammalian DNA induce CpG-independent, direct cytotoxic effects in cell cultures and in mice. J Gene Med. 2006, 8(8), 998-1007.
  13. Yew NS and Cheng SH. Reducing the immune stimulatory activity of CpG-containing plasmid DNA vectors for non-viral gene therapy. Expert Opin Drug Deliv. 2004, 1(1), 115-25.
  14. Ho MW, Cummins J and Saunders PT. GM food nightmare unfolding in the regulatory sham. Microbial Ecology in Health and Disease 2007, 19(2), 66 – 77.
  15. List of I-SIS submissions to USDA and other US regulatory agencies.
    1. USDA Poised to Deregulate Illegal GM Rice, SiS 32, 2006.
    2. USDA Proposes to Deregulate Its Own Transgenic Plum, SiS 31, 2006.
    3. GM Sugar Beet Gone Sour, SiS 25, 2005.
    4. GM Eucalyptus Environmental Assessment Irregular, SiS 35, 2007
    5. Dangerous Field Test of Non-pathogenic GM Bacteria, SiS 35, 2007.
    6. Deregulation of Glyphosate Tolerant Creeping Bentgrass Out of Questio
    7. Death Domains in New Bio-pesticides, SiS 26, 2005.
    8. Best Practice in the Design of GM Crops, I-SIS Report, 2000, https://www.i-sis.org.uk/gmdesign.php
    9. GM Maize 59122 Not Safe, SiS 34, 2007.
    10. GM Safflower with Human Pro-Insulin, SiS 35, 2007.
    11. MON88017 Another MON863?, I-SIS Report, 2005, https://www.i-sis.org.uk/mon.php
    12. Antibodies from Hybrid GM Tobacco Plants, SiS 35, 2007.
    13. Field-testing Bacterial Pathogens and Fungus, I-SIS Report, 2005, https://www.i-sis.org.uk/fieldTest.php
    14. Comment on Assessment ReportC/GB/02/M3/03, I-SIS Report, 2004, https://www.i-sis.org.uk/CaliforniaLetter.php
    15. Transgenic Pink Bollworms FONSI?, I-SIS Report, 2001, https://www.i-sis.org.uk/pinkbollworms.php
    16. Comments on: Environment Assessment: Confined field study of a ..., , I-SIS Report 2001, https://www.i-sis.org.uk/bollworm.php
    17. ISIS News no.9/10 - Stop Release of GM Insects. I-SIS Report, 2001 https://www.i-sis.org.uk/isisnews/i-sisnews9-2.php
    18. piggyBac a name to remember, I-SIS Report, 2001, https://www.i-sis.org.uk/piggybac-pr.php
    19. No Bt Resistance? SiS 20, 2003.
    20. Pharm Crop Products In US Market, SiS 23, 2004.
    21. More on Bt Resistance, I-SIS Report, 2003, https://www.i-sis.org.uk/MoreBtresistance.php
    22. The full significance of theA normally harmless bean protein, a ..., I-SIS Submission to many regulatory bodies, 2005, https://www.i-sis.org.uk/TPTMMI.php, also Transgenic Pea that Made Mice Ill, SiS 29, 2006
    23. Why Not Transgenic High Lysine Maize, SiS 29, 2006.
    24. No to GM Oilseed Rape GT73, SiS 24, 2004.
    25. Chronicle of An Ecological Disaster Foretold, SiS 18, 2003.
    26. ISP Bid to Stop US 'Rubber-Stamping' Transgene Contamination, SiS 25, 2005.
    27. GM Pharmaceuticals from Common Green Alga, SiS 28, 2005.
    28. Terminator insects unleash genome invaders with wings, I-SIS Report, 2001, https://www.i-sis.org.uk/terminsects-pr.php
    29. Terminator Insects – The Killing of Females, I-SIS Report, 2001, https://www.i-sis.org.uk/sterileinsect.php
    30. Is FDA Promoting or Regulating Cloned Meat and Milk? SiS 33, 2007.
    31. Bt Toxins in Genetically Modified Crops: Regulation by Deceit, SiS 22, 2004.
    32. GM Crops and Microbes for Health or Public Health Hazards?, SiS 33, 2007.
    33. GM Crops for Health? I-SIS Report, 2006, https://www.i-sis.org.uk/GM_Crops_for_Health.php
    34. Moratorium on all GM Trees and Ban on GM Forest Trees, I-SIS Report, 2007, https://www.i-sis.org.uk/Moratorium_on_all_GM_Trees.php
  16. Cummins J and Ho MW. Approval of GM crops illegal, US federal courts rule. Science in Society 34, 24, 2007.
  17. Ho MW. No to GMOs, no to GM science. Science in Society 35.
  18. Ho MW, Cummins J, Burcher S, Gala R, Lim LC, et al. GM Science Exposed: Hazards Ignored, Fraud, Regulatory Sham, Violation of Farmers’ Rights, Compilation from Science in Society archives, 2003-2007, I-SIS CD Book, https://www.i-sis.org.uk/includes/frontpage11.htm