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[SANET-MG] added some useful refernces



April 2, 2004
Human lysozyme and lactoferrin therapeutic proteins also have been implicated in
pathological condition
Prof. Joe Cummins
e-mail; jcummins@uwo.ca
Recently crop plants modified with the therapeutic proteins lysozyme and/or
lactoferrin  have been tested in the field. Rice modified with lysozyme and
lactoferrin has been put forward for commercial production(1). Lysozyme
protects us from the  danger of bacterial infection. It is an enzyme that
attacks the protective cell walls of bacteria. Bacteria build a tough skin of
carbohydrate chains, interlocked by short peptide strands, that braces their
delicate membrane against the cell's high osmotic pressure. Lysozyme breaks
these carbohydrate chains, destroying the structural integrity of the cell
wall. The bacteria burst under their own internal osmotic  pressure. Lysozyme
is present in bacteria and animals alike, birds egg lysozyme is a powerful food
allergen but human lysozyme is less likely to cause allergy.  Lactoferrin is  a
protein that participates in regulation of immune functions and  controls
pathogens by binding iron required for bacterial growth. Both lysozyme and
lactoferrin are present in mother?s milk and both are used to treat infections.
In spite of their value in controlling infection there are pathological
conditions associated with the proteins or genetic variants of the proteins.
These pathological  associations seem to have been overlooked by the promoters
of the biopharmaceutical  applications of  proteins. However, the pathological
side effects should have been considered because food crops may become polluted
with the genes for the proteins and the proteins. The references below may
provide useful information for those  questioning the production of the
proteins in food crops.
        Lysozyme provides effective contol of many infections  but the protein may ,as
well, contribute to the pathology of pulmonary emphysema by binding to elastic
fibers  which undergo breakdown in the disease (2). Hereditary  systemic
amyloidosis is caused by mutant forms of  cell proteins deposited as amyloid
fibrils, the mutant cell proteins include lysozyme  or apolipoprotein or
fibrinogen (3). The lysozyme related  disease was provoked by a single mutation
of  tryptophane to arginine. The disease is inherited as dominant gene and
frequently leads to death at mid-life (4). A lactoferin mutant  has been
implicated as a cause of amyloidosis accompanied by trichiasis (a common vision
threatening condition of the eylid ). The lactoferrin mutant resulted from a
single change from  glutamic to aspartic acid near the end of the protein
molecule (5).Lactoferrin has also been found to be implicated  in forms of
autoimmune diseases including systemic lupus  erythematosis and rheumatoid
arthritis (6) or in rheumatoid arthritis associated with vaculitis
(inflammation of blood vessels) (7). Along with the effects related to
pathology of the immune system , the wild type  lactoferrin and  lysozyme
proteins are associated with amyloid formation  related to diseases such
Alzheimer?s disease, Amyotrophic Lateral Sclerosis ( Lou Gehrig's Disease) or
Down?s Syndrome.  Lactoferrin is associated with other proteins  in amyloid
(8,9), while lysozyme alone is a precursor for amyloid fibrils (10). An
extensive  number of  different proteins  have been identified in amyloid
fibrils and consequences  of feeding elevated human lysozyme and lactoferrin ,
or for that matter  the other amyloid precursor proteins have not been
reported.
        Production of  human lysozyme  and lactiferrin in food crops such as rice,
barley or maize has been promoted as if  the products are purely beneficial
without  harmful side-effects. However, there is evidence that both normal and
mutant forms of  the proteins are associated  with serious detrimental human
diseases. In particular the synthetic forms of the human genes used in crop
modification  are modified both in codons and frequently amino acids to enhance
production of the proteins in plants and these alterations  are seldom
thoroughly tested. Mutations of the human genes in the plants are not normally
identified unless they  eliminate production of the protein. There seems to be
a culture  that puts optimism ahead of experiment and distains labeling  of
products, crop production or field tests so that deleterious side effects of
the crops or their products cannot be identified.
Why is the evidence of harmful side effects and dangerous mutant forms presented
at the safety evaluation of  field tests and  production sites? The answer
seems to be that both proponents and regulators do not wish to alarm the
public. Indeed, if and when the matter is brought up regulators and proponents
will unleash teams of vicious lawyers whose job is to shift the burden of proof
to those who mention harmful or  dangerous side effects . Nevertheless, if and
when the dangerous tests or crop productions are undertaken  people who are
effected should  begin to  notice amyloidosis  or autoimmune diseases including
lupus and  arthritis. The main geographical areas of concern are California
where  biopharmaceutical rice is being ?tested? on a large scale and in
Washington state where large plots of  biopharmaceutical barley is being
?tested?.
References
1.      Cummins,J. ?Rice with human genes: pharming in California? 2003 1-4pp
http://www.indsp.org/
2.      CANTOR,J.,SHTEYNGART,B., CERRETA,J. AND  TURINO,G. ?The Effect of Lysozyme on
Elastase-Mediated Injury? 2002 Exp Biol Med  227:108?13
3.      Hawkins,P. ?Hereditary systemic amyloidosis with renal involvement?2003 J.
Nephrol. 16,443-8
4.       VALLELX,S.,DRUNAT,S.,PHILIT,J.,
ADOUE,D.,PIETTE,J.,DROZ,D.,MACGREGOR,B.,CANET,D., DELPECH,M. and GRATEAU,G.?
Hereditary renal amyloidosis caused by a new variant lysozyme W64R in a French
family? 2002 Kidney International 61,907-12
5.       Ando,Y. ?Analyses of pathogenesis and therapeutic approaches for hereditary
amyloidosis? 2003 Rinsho Byori 51,530-5
6.      Nassberger L, Hultquist R and  Sturfelt G. ?Occurrence of anti-lactoferrin
antibodies in patients with systemic lupus erythematosus, hydralazine-induced
lupus, and rheumatoid arthritis.? 1994 Scand J Rheumatol. 23,206-10
7.      Coremans I, Hagen E, Daha M, van der Woude F, van der Voort E, Kleijburgvan
der Keur C, Breedveld F. ?Antilactoferrin antibodies in patients with
rheumatoid arthritis are associated with vasculitis.? 1992 Arthritis Rheum.
35,1466-75
8.      Nilsson,M. and Dobson,C. ?In vitro characterization of lactoferrin
aggregation and amyloid formation? 2003 Biochemistry 42,375-82
9.      Postuma R, Martins R, Cappai R, Beyreuther K, Masters C, Strickland D, Mok,S
and Small D. ?Effects of the amyloid protein precursor of Alzheimer's disease
and other ligands of the LDL receptor-related protein on neurite outgrowth from
sympathetic neurons in culture.? 1998 FEBS Lett. 428,13-6
10.     Niraula,T,  Konno,T,  Li,H., Yamada,H, Akasaka,K. and  Tachibana,H.
?Pressure-dissociable reversible assembly of intrinsically denatured lysozyme
is a precursor for amyloid fibers? 2004 Proc. Natnl.Acad.Sci.USA 101, 4089?93

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