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pharming in California



December 17, 2003

Prof. Joe Cummins

e-mail: jcummins@uwo.ca <mailto:jcummins@uwo.ca>

“Rice with human genes: pharming in California”

In 2002 Greenpeace disclosed the location of a site in Northern
California where rice plants modified with the human genes lactoferrin
and lysozyme were being tested. Lactoferrin acts against bacterial
pathogens by preventing them from taking up iron needed for their
growth, while lysozyme acts against the cell wall material of the
bacterial pathogens. The biopharmaceutical rice crop was being tested by
a California biotechnology company, Applied Phytologics.(1,2). In spite
of the intense public scrutiny efforts are being made to continue the
open field testing of the rice plants modified with two human genes. The
Greenpeace disclosure created an avalanche of concern from the public
and from both conventional and organic rice farmers who feared
contamination of their crops would lead to economic disaster. Washington
State University field tested barley altered with human genes for
lactoferrin, lysozyme, antitrypsin and antithrombin (3) but that field
test release was not acknowledged by the public even though it posed a
threat to both conventional and organic production of beer and animal
feed. Maize modified with human lactoferrin was field tested by Biochem
SA company and by Meristem Therapeutics company in France (4). The
French field tests do not appear to have been acknowledged by the public
even though such tests threatened both conventional and organic maize
production on the continent.

Most of the field testing of genetically modified (GM) biopharmaceutical
crops appears to have been done in the United States (US), France and
Canada. US completed 315 such tests between 1991 and 2002, the main
modified organisms included maize, rice soy and Tobacco Mosaic Virus
.The majority of tests were done in Nebraska, Hawaii, Wisconsin and
Puerto Rico (5). Canada completed 53 field tests of biopharmaceutical
crops between 1995 and 2003 (6) while France completed 24 field tests on
GM biopharmaceutical crops 1995 and 1998 (4). The US and Canadian field
trials of GM biopharmaceuticals are clouded by the use of confidential
business information (CBI) designations which hide the details of the
gene construction and the exact locations of the field tests. Those
neighboring the field trials have no means of relating any illness or
discomfort experienced from exposure to polluted plant debris or pollen,
or to contaminated ground or surface water escaping from the test site
to the GM biopharmaceuticals being tested, certainly an unjust situation.

Returning to the rice GM biopharmaceutical genetic construct, like other
biopharmaceuticals produced in seed , the construct includes the human
genes for the primary biopharmaceutical protein driven by a seed
specific promoter and the protein is expressed with a fusion polypeptide
(the signal peptide) that causes the fusion protein to accumulate in a
cell compartment such as a vacuole or seed endosperm (7). Human
lactoferrin produced in plants has been described (8). Human lysozyme
produced in plants has been patented as a biopestide to protect plants
against fungal and animal pests (9). Human lysozyme produced in rice has
been localized to the endosperm of transgenic rice (10,11).

Expression of human milk proteins in plants has been discussed by
nutrition authorities who have maintained that such products should be
tested using feeding experiments in rats then human volunteers(12). The
problem of inadvertent exposure to the products by consuming crops
contaminated by the products by accidental spread of pollen or seeds was
not discussed. Chicks were fed rice bearing human lysozyme and
lactoferrin and the rice was found to have antibiotic like properties (13).

Lactoferrin is a protein that participates in regulation of immune
functions and contols pathogens by binding iron required for bacterial
growth. Lactoferrin has been in asthma with fatal outcomes (14).
Lactoferrin variants has been associated with localized juvenile
periodontitis (15). It has been suggested that milk lactoferrin
possesses allergenic sites (16). Lactoferrin is a protein modified by
glycosylation, a modificatoion

that contributes to enzyme activity and to allergenicity of the protein,
human lactoferrin was found to be glycosylated differently from the
human transgene protein produced in tobacco(17).The different pattern of
glycosylation observed in human and the tobacco transgene product should
not be considered insignificant until full studies of allergenicity of
the transgenic protein are completed. Chicken egg lysozyme is a well
known potent food allergen (18) while human lysozyme is clearly not
allergenic. Like lactoferrin , lysozyyme is a glycosylated enzyme and
variants of human lysozyme have been studied (19). The glycosylation
patterns of the transgenic enzyme produced in plants seems to have been
neglected even though that pattern will influence allergenicity of the
product. Clearly, both transgenic lactoferrin and transgenic lysozyme
are potentially hazardous to human health and such concerns should be
made clear to those exposed to the field test sites or those living nearby.

Transgenic rice crops may spread pollen or seeds to adjacent fields thus
contaminating those crops. Rice is known to be somewhat self fertilizing
but clearly capable of spreading both pollen and seeds to nearby fields.
Gene flow has been studied between commercial rice and weedy red rice
(20,21). These studies suggest that transgenes may spread to
non-transgenic rice. Once established the transgenes may be difficult to
impossible to eliminate. Organic and conventional rice producers have a
legitimate concern over secretive field testing of transgenic rice.

Transgenic glufosinate resistant rice (Liberty Link) was de-regulated in
the US during 1999, the Animal Plant Food Inspection Service (APHIS) of
USDA guessed that the transgenic rice would not pollinate weedy red rice
but even if it did the weed could be eliminated using herbicides other
than glufosinate (22). Concern over the threat of transgenic rice to
organic and conventional producers was outlined and the probable
instability of transgenic rice do to soma clonal variability was
discussed (23).

Recently, recombinant biopharmaceutical production in transgenic crops
has been actively promoted , in spite of incidents of contamination of
food production observed during field test releases of the transgenic
biopharmaceutical crops (24,25). Production of the biopharmaceutical
crops in confined greenhouses was deemed un-economic even though such
production provides the barest essentials for protecting the food crops
from genetic pollution. The unacceptable practice deeming secretive
field tests to be confidential business information must be stopped.
Both testing and production of transgenic crops producing
biopharmaceuticals should be restricted to confined greenhouses that
provide isolation from the atmosphere and groundwater. Transgenic crops
bearing human milk proteins are promoted because “mother’s” milk is
presumed safe for all, but the crop transgenic “mother’s milk” is far
from identical to the real thing. Furthermore , the transgenic milk
crops will soon be followed by anticoagulants, human growth hormone,
antibodies and a range of other biopharmaceutical products all
potentially significantly different from the original products. The
biopharmaceutical dam may soon burst leaving the human population with
an array of hidden medications in their food.

References

  1. Greenpeace Press Release “Crop producing human proteins found
     growing in open field test” 2001
     http://www.greenpeaceusa.org/media/press_releases/01_09_06text.htm
  2. Wilson,K. “Crop Producing Human Protein Found Growing in Open
     Field Test”

2002 Synthesis/Regeneration http://www.greens.org/s-r/28/28-26.html

3. APHIS field test permits for bio-pharm crops “Washington State
University” 2001 Barley
http://www.colostate.edu/programs/lifesciences/TransgenicCrops/pharmpermits.html

4. France “Total number of summary notifications circulated” 2003
http://biotech.jrc.it/deliberate/FR.asp

5. Freese,B. “Manufacturing drugs and chemical crops :biopharming poses
new threats to consumers, farmers, food companies and the
environment”2002 Friends of the Earth Genetically Engineered Food Alert
pp1-98

6 Canadian Food Inspection Agency “confined field trials Canada
pharmaceutical “ 2003

http://www.inspection.gc.ca/english/plaveg/bio/triesse.shtml

7. Lemaux,P,Cho,M. and Buchanan,B. “Production of protein in plant
seeds” 2003 US Patent 6,642,437 pp 1-48

8. Legrand,D.,Salmon,D.,Spik,G.,Gruber,V.,Bournat,P. and Bertrand,M.
“Recombinant lactoferrin ,methods of production from plants and uses”
2003 US Patent 6,569,831 pp 1-39

9.Hain,R. and Stenzel,K. “Use of lysozyme gene structure in plants to
increase resistance” 1994 US Patent 5,349,122 pp 1-24

10. Yang,D.,Guo,F.,Haung,N. and Watkins,S. “Expression and localization
of human lysozyme in the endosperm of transgenic rice” 2003 Planta
216,597-603

11. Huang,J, Nandi,S, Wu,L, Yalda1,D, Bartley,G, Rodriguez,R.,
Lonnerda,B. and Huang,N. “Expression of natural antimicrobial human
lysozyme in rice grains” 2002 Transgenic Research 11, 229–39

12 Lonnerdal,B. “Expression of human milk protein in plants”2002 Journal
of the American College of Nutrition” 3,218s-221s

13. Humphrey,B.,Haung,N. and Klasing,K. “Rice expressing lactoferrin and
lysozyme has antibiotic like properties when fed to chicks” 2002 J.
Nutr. 132,1214-18

14. Tsokos,M. and Paulsen,E. “Expression of pulmonary lactoferrin in
sudden onset and slow onset asthma with fatal outcome” 2002 Virchows
Arch. 441,494-99

15. Velliyagounder K, Kaplan J, Furgang D, Legarda D, Diamond G, Parkin
R. and

Fine D. “One of two human lactoferrin variants exhibits increased
antibacterial and transcriptional activation activities and is
associated with localized juvenile periodontitis.” 2003 Infect Immun.
71,6141-7

16. Sharma S, Kumar P, Betzel C. and Singh T. “Structure and function of
proteins involved in milk allergies” 2001 J Chromatogr B Biomed Sci
Appl. 756,183-7

17. Samyn-Petit,B, Wajda Dubos,J, Chirat,F,Coddeville,B, Demaizieres,G,
Farrer,S, Slomianny,M, Theisen,M and Delannoy,P. “Comparative analysis
of the site-specific N-glycosylation of human lactoferrin produced in
maize and tobacco plants” 2003 European Journal of Biochemistry 270,3235-42

18. Yoshinori ,Y and Zhang,J “Comparative Studies on Antigenicity and
Allergenicity of Native and Denatured Egg White Proteins” 2002 J. Agric.
Food Chem., 50 , 2679 -83

19. MELCHER,R, HILLEBRAND,A, BAHR,U, SCHRODER,B, KARAS,M and HASILIK,A.
“Glycosylation-site-selective synthesis of N-acetyl-lactosamine repeats in

bis-glycosylated human lysozyme” 2000 Biochem. J. 348, 507-15

20. Newswise “Gene flow patterns may give clues to managing promiscuous
plants” 2002 pp1-2 http://www.newswise.com/p/articles/view/?id=GENEFLOW.UAR

21.Song,Z.,Lu,B.,Zhu,Y and Chen,J. “Pollen competition between
cultivated and wild rice species” 2002 New Phyologist 153,289-96

22.APHIS “determination of non-regulated status for glufosinate tolerant
rice” 1999 pp1-25

http://www.aphis.usda.gov/brs/aphisdocs/98_32901p.pd

23. Cummins,J. “Liberty Link Rice: Herbicide Tolerant Rice for the
Masses” 2001 pp1-4

http://www.amberwaves.org/web_articles/joecummins.html

24. Ma,J., Drake,P and Christou,P. “THE PRODUCTION OF RECOMBINANT
PHARMACEUTICALPROTEINS IN PLANTS” 2003 Nature Reviews of Genetics 4, 794-806

25. Peterson,R. and Arntzen,C. “On risk and plant based
biopharmaceuticals” 2004, Trends in Biotechnology in press
doi:10.1016/j.tibtech.2003.11.007
<http://dx.doi.org/10.1016/j.tibtech.2003.11.007>

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