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[SANET-MG] pharm crops should be limited to cell culture



October 23, 2004

Prof. Joe Cummins

“Transgenic pharmaceutical producing Plants should be limited to
laboratory based cell culture production”

Proteins from humans and animals are widely employed in research,
medicine and in industry, but preparing such proteins from their
original sources is expensive and able to cause injury to humans and
animals through contamination of the target proteins with viruses,
cancer causing DNA or prions (proteins causing mad cow disease or human
Creutzfeldt-Jakob disease).Proteins such as monoclonal antibodies are
not found naturally and large scale production of them is expensive.
Molecular farming (pharming) using crop plants to produce recombinant
proteins has gained wider acceptance because it can be relatively
inexpensive and it avoids spread of animal viruses and prions. The
options available for producing recombinant proteins include bacteria,
yeast or other fungi, mammalian cell culture, transgenic animals , plant
cell culture and transgenic crops . Bacteria and fungi do produce
recombinant proteins but protein modification by sugars and other
molecules are lacking or incorrect potentially leading to function and
immune problems. Mammalian cell culture and transgenic animals produce
correctly modified proteins but are expensive and plagued by the
contaminants mentioned above. Plant cell culture and crops do not modify
recombinant proteins perfectly but they do produce product at low cost
and free from the contaminants injuring animals and people(1). Field
production of recombinant pharmaceutical proteins in field crops is
actively promoted in academe in government and claimed to be production
of very low cost, however, that kind of public relations ignores the
huge costs flowing from the contamination of food crops and weeds with
the genes for the recombinant proteins or for contaminating surface and
ground water with the proteins. Pollution of a food crop with genes for
pharmaceutical proteins creates s disastrous impacts on both exports and
internal production of the crop, but in spite of those legitimate
concerns field production of recombinant protein is promoted (2)
Promoters of pharming maintain that in spite of the extensive pollution
of food crops with genes for pharmaceutical proteins little or no harm
will be inflicted on the public (3). As will be discussed below , the
field tests are undertaken with unnecessary secrecy and little effort
has been made to study the impact of such secret tests on humans and
animals even though the end point for some exposures may be death.

The field test releases of pharmaceutical proteins are listed by the
Information System for Biotechnology. 84 field release permits for
recombinant pharmaceuticals in crop plants or tier viruses between the
years 1991 and 2004 are included. Crops employed in the tests include
corn, barley, tobacco, safflower, sugar cane, rice, tomato , wheat and
rapeseed Along with the food crops modified plant viruses were used in a
number of the tests. For the most part the locations of the test sites
and transgenes involved in the test were designated confidential
business information (CBI) The field test releases are mainly designated
CBI but in some instances potential carcinogens such as insulin like
growth factor or immune sensitizing proteins such as aprotinin (produced
using Tobacco Mosaic Virus)are identified (4). There is little real
justification for concealing the location and nature of hazardous field
releases. Bill Freese of Friends of the Earth listed 315 field tests of
crops and viruses modified with genes for pharmaceutical proteins
between the years 1991 and 2002 The field releases were mainly located
in Nebraska, Hawaii and Puerto Rico with an additional 33 states
undertaking a few tests each (5). The salient feature of the numerous
tests is the veil of secrecy around the test sites and even the nature
of the potent pharmaceuticals being tested. Such secrecy is usually
justified by a fear of vandalism, however adequate security for the
sites is not even contemplated. The claim that the tests are harmless to
humans and animals is clearly empty public relations as little effort
has been made to monitor the test sites or even to inform potential
victims of the tests even though many of the crops or viruses employed
in producing the pharmaceutical proteins are well know to spread widely
and permanently in the environment.

In the United States commercial production of recombinant proteins from
the field tests releases is allowed. For that reason field test sites
are frequently are as large as fifty or one hundred acres, allowing full
production of the valuable pharmaceuticals without undertaking the
expensive and time consuming deregulation required of food crops. Thus,
secretive production of dangerous pharmaceuticals is undertaken far from
public scrutiny and rigorous regulation. For example, secret field
testing of plant-based aprotinin could result in severe or fatal
anaphylaxis, either in a brief exposure in the maize field of someone
previously treated during surgery, or exposure of someone exposed to the
maize field followed by treatment during surgery (6). Fatal anaphylaxis
related to aprotinin after application of fibrin glue has been reported
(7).Currently, aprotinin is used extensively in surgery but with a
restriction that sensitization will result and that the patient should
not be exposed again to the potent antigen In spite of the potential
hazard of aprotinin Sigma chemical company markets aprotinin based on
production using a modified plant virus (8). Clearly, regulation of
testing and production of pharmaceutical proteins seems to be
libertarian in practice, with little regard for health and safety of
bystanders to the production of the pharmaceutical .

It is often claimed that the safety of transgenic crops producing
recombinant pharmaceuticals is fully protected by employing crops that
do not produce pollen or by providing an extended buffer zone around the
production sites. Little or no though has been given to pollution of
surface and groundwater by the pharmaceutical proteins in the field
plots. However, pharmaceutical proteins are released from modified
plants to the groundwater (9). Regulators seem to ignore the pollution
of surface and groundwater by root exudates, leaf and stem wounding and
by debris during production . Pharmaceutical proteins such as the
cytokine interleukin 10 potently suppress the immune system in minute
quantities but do not seem to be monitored in surface and ground water
during field tests (10).

The risks of numerous pharmaceutical proteins , including vaccines and
therapeutic antibodies along with history of careless field test
releases is recounted in a number of reviews (11,12,13,14).

In spite of the tunnel vision of powerful proponents who promote field
test releaser and production of recombinant pharmaceuticals, the risks
of human and environmental injury from such productions outweighs any
benefit from the production. The touted low costs of production will
disappear in the face of liability for human and environmental damage..
The high value recombinant pharmaceuticals can be produced at moderate
cost in suspension cell culture of plant cells as is shown in the
production of human macrophage stimulating factor (15) or human milk
protein (16). However, the glycosylation (sugar addition to proteins)
pattern of the recombinant proteins synthesized in plants and plant cell
culture still poses a problem (17). The glycosylation pattern may effect
both the activity of the protein and its immunological response (for
example sensitization). The moss plant Pscomtrella , unlike the food
crop plants, has been found suitable for allele “knock out” and targeted
allele alteration(17). This capability has allowed production of
plant-made glycosylated pharmaceuticals with non allergenic glycans.

In conclusion, secretive field trial production of recombinant
pharmaceuticals using crop plants or their viruses provides an
intolerable risk to food production, human bystanders and the
environment. Such field tests releases should be banned and production
should be restricted to laboratory based plant cell culture.

References

1.Ma,J,Drake,P. and Christou,P. The production of recombinant
pharmaceutical proteins in plants 2003 Nature Reviews Genetics 4,794-805

2.Collis,B. Farmers to pharmas 2004 Nature 429,A10-A13

3.Miller,H. Will we reap what biopharming sows? 2003 Nature
Biotechnology 21,480-1

4.Information Systems for Biotechnology Field test release permits data
base U.S-. pharmaceutical proteins 2004
http://www.isb.vt.edu/2002menu/regulatory_information.cfm

5. Freese,B. Manufacturing drugs and chemicals in crops 2002 Friends of
the Earth 2002 pp1-98
http://www.foe.org/camps/comm/safefood/biopharm/BIOPHARM_REPORT.pdf

6. Cummins,J. Pharm crop products in US market 2004 http://www.i-sis.org.uk/

7.Oswald,A,Joly,L,Gury,C,Disdet,M,Leduc,V. and Kanny,G. Fatal
intraoperative anaphylaxis related to aprotinin after local application
of fibrin glue 2003 Anesthesiology 99,762-3

8 Sigma Aldrich Product A6103 Aprotinin, recombinant bovine.
http://www.sigmaaldrich.com/

9. Cummins,J. Release of pharmaceutical proteins from modified plants to
hydroponic solutions and to groundwater 2003
http://www.indsp.org/Pharmprotein.php

10.Cummins,J. Poison pharm crops near you 2002 http://www.i-sis.org.uk/

11. Ho,M. Pharmageddon 2003 http://www.i-sis.org.uk/

12.Cummins,J. Risks of edible transgenic vaccines 2003
http://www.i-sis.org.uk/

13.Cummins,J. Pharm crops for vaccines and therapeutic antibodies 2004

http://www.i-sis.org.uk/

14. Cummins,J. Rice with human genes; pharming in California 2003
http://www.indsp.org/Pharmprotein.php

15. Kim,Y,Kwon,T, and SikY. Direct transfer and expression of human
GM-CSF in tobacco suspension cell using Agrobacterium-mediated transfer
system 2004 Plant Cell, Tissue and Organ Culture 78: 133–8

16. Girard,L, Bastin,M. and Courtois,D. Expression of the human milk
protein sCD14 in tobacco plant cell culture 2004 Plant Cell, Tissue and
Organ Culture 78: 253–60

17. Gomord,V,Sourrouille,C, Fitchette,A, Bardor,M,Pagny,S, Lerouge,P.
and Faye,L. Production and glycosylation of plant-made pharmaceuticals
Production and glycosylation of plant-made pharmaceuticals: the
antibodies as a challenge 2004 Plant Biotechnology Journal 2, 83–100

18. Koprivova,A, Stemmer,C, Altmann , Hoffmann,A, Kopriva,S, Gorr,G,
Reski,R. and Decker,E. Targeted knockouts of Physcomitrella lacking
plantspecific immunogenic N –glycans 2004 Plant Biotechnology Journal 2
, 517–23

.

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