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Plant Biopharming ?
Plant biopharming is defined as the farming of
transgenic plants genetically modified to produce
“humanised” pharmaceutical substances for use in
humans. The growing of crops that have been
genetically modified to produce pharmaceutical
compounds for use by humans: “common crop plants
such as corn and tobacco increasingly being
programmed with recombinant DNA techniques to
produce high-value-added pharmaceuticals, a process
dubbed ‘biopharming’. The plants are harvested and
the drug is then extracted and purified” (Miller 2003:
480).
Conti..
Biopharming is one of several methods that can be used toproduce the class of drugs known as biopharmaceuticals:“these drugs, known as biologics, include any protein, virus,therapeutic serum, vaccine and blood component” (Elbehri2005: 18).
Biopharming is also known as “molecular farming”.Molecular farming is the production of pharmaceuticallyimportant and commercially valuable proteins in plants(Franken et al., 1997).
The most common plants currently being researched forbiopharming include corn, soybeans, rice, tobacco, andpotatoes (see Table 1), modified to produce the substance,usually a protein, vitamins, amino acids in their fruit, leaves,seeds or tubers, etc.
Brief HistoryYear Development Reference
1986 First plant -derived recombinant
therapeutic protein- human GH in
tobacco & sunflower
A. Barta, D. Thompson et al.,
1989 First plant -derived recombinant
antibody –full-sized IgG in
tobacco.
A. Hiatt, K. Bowdish
1990 First native human protein
produced in plants –human serum
albumin in tobacco & potato.
P. C. Sijmons et al.
1992 First plant derived vaccine candidate –hepatitis B virus
surface antigen in tobacco
H. S. Meson, D. M. Lam
1995 Secretory IgA produced in tobacco. J. K. Ma, A. Hiatt, M. Hein et
al.
1996 First plant derived protein polymer-
artificial elastin in tobacco
X. Zhang, D. W. Urry, H.
Daniel
Brief HistoryYear Development Reference
1997 First clinical trial using recombinant
bacterial antigen delivered in a
transgenic potato
C. O. Tacket et al.
1997 Commercial production of avidin
in maize
E. E. Hood et al.
2000 Human GH produced in tobacco
chloroplast
J. M. Staub et al.
2003 Expression and assembly of a
functional antibody
in algae.
S. P. Mayfield, S. E. Franklin
et al.
2003 Commercial production of bovine
trypsin in maize.
S. L. Woodard et al.
Concept of Biopharming
The concept of biopharming is not new. Genetic modification
has been applied to plants for decades in order to improve
their nutritional value and agronomic traits (yield, pest and
drought resistance, etc.).
The production of high value added substances through gene
manipulation is a logical, straight forward extension.
The energy for product synthesis comes from the sun, and
the primary raw materials are water and carbon dioxide and if
it becomes necessary to expand production, it is much easier
to plant a few additional hectares than to build a new bricks
and mortar manufacturing facility.
Conti..
Another major advantage is that vaccines produced in this
way will be designed to be heat stable so that no
refrigeration chain from manufacturer to patient will be
required.
This would have a great application in developing
countries, especially in the tropics and throughout Asia and
Africa.
Globally, several companies are involved in biopharming,
about half have products in clinical trials.
The spectrum of products is broad, ranging from the
prevention of tooth decay and the common cold to
treatments for cancer and cystic fibrosis.
• Biopharming offers tremendous advantages over
traditional methods for producing pharmaceuticals.
There is great potential for reducing the costs of
production.
• Major drivers for the development of biopharming
internationally are its potential to lower the costs of drug
production, the greater ease of upscaling and
downscaling production, an anticipated shortage of
manufacturing capacity using other production methods,
the potential to address some of the limitations of other
production methods, and the desire to strengthen or
evade patent restrictions.
Conti..
Why Plants ?
According to Horn et al., 2004
Significantly lower production costs than with transgenic
animals, fermentation or bioreactors;
Infrastructure and expertise already exists for the planting,
harvesting and processing of plant material;
Plants do not contain known human pathogens (such as
virions, etc.) That could contaminate the final product;
Plant cells can direct proteins to environments that reduce
degradation and therefore increase stability.
Some of Plants Used for Biopharmaceutical
ProductionSr. No. Category Plants used
1 Model plant Arabidopsis thaliana
2 Leafy crops Tobacco, lettuce, alfalfa, clover
3 Cereals Maize, rice, wheat, barley
4 Legumes Soybean, pea, pigeon pea
5 Fruits and vegetables Potato, carrot, tomato, banana
6 Oil crops Oilseed Rape Seed, Camelina sativa
7 Simple plants Lemna sp. Physcomitrella patens,
Marchantia polymorpha, Chlamidomonas
reinhardtii
Sibila Jelaska et al. 2005
Bio-pharmed crops
Drug/Chemical Use Test Crop
Laccase Textiles, Adhesives Corn
Folic acid Vitamin Tomatoes
Erythropoeitin Anemia Tobacco
Essential fatty acids Cell membrane production Soybeans
SARS vaccine Immunization Tomato
Vaccine against pollen allergies Immunization Rice
Traveler’s and other Diarrheas Immunization/
Drug
Rice, Potatoes
and Corn
Insulin Treatment of Diabetes Safflower
Insulin-like Growth Factors Diabetes, Growth,
Carcinogen
Rice
Recombinant Proteins Expressed in Plants
According to Horn et al., 2004
Parental Therapeutics and Pharmaceutical
Intermediates
Antibody in plants
Edible Vaccines
Industrial proteins
Edible vaccine
• Concept of edible vaccine got impetus after expression of
hepatitis B surface antigen in tobacco plants (Mason et
al., 1992)
• The first reported edible vaccine was a surface protein
from streptococcus expressed in tobacco leaves. (Mason
and Arntzen, 1995)
Why to Choose Plants for Vaccines?
No Ethical Issues
Ability to Express Combined
Transgenes
By Sexual Crossing
Flexible Production Size,
Low Cost
Large Scale Production in
Biotech-Corps / Agriculture
Easy to Taken, No Phobia to
Injection
Easy Transport
as Fruits, Leaves and
Seeds, More Viability
Correct Folding and
Modification of Proteins in ER
Low Contamination
Risk by Bacterial Enzymes, Toxins,
Fungus and Viruses
Examples of edible vaccinesVaccines Vector used Disease /conditions
for which it is used
Hepatitis B Virus Tobacco, Potato,
Lettuce
Hepatitis B
Norwalk virus Tobacco, Potato Diarrhoea, Nausea,
Rabies virus Tabacco Rabies
Transmissible
gastroenteritis
Corona virus
Tobacco, Maize Gastroenteritis
Rabbit hemorrhagic
disease virus
Potato Hemorrhage
HIV virus Tomato AIDS
Vibrio cholerae Potato Cholera
Neeraj et al. (2008)
TRANSGENIC TOMATO
See I lost my
shelf life how can
I improve my
shelf life ?
Look at me they are
making transgenic
tomato so that I can
improve my shelf life.
WOW!!! So excited
Golden Rice
Purported to be the solution to the problem of Vitamin A
deficiency in developing countries
Developed in 1999 by Swiss and German scientists, led by
Ingo Potrykus
-Potrykus has accused GM opponents of “crimes against humanity”
Produced by splicing two daffodil and one bacterial gene
into japonica rice, a variety adapted for temperate climates
In 2011, First time plantings in India with Philippines and
Vietnam
But crop not yet adapted to local climates in developing
countries
Produces β-carotene, which the body converts into Vitamin
A (in the absence of other nutritional deficiencies - such as
zinc, protein, and fats - and in individuals not suffering from
diarrhea)
Β-carotene is a pro-oxidant, which may be carcinogenic
The latest…
• Syngenta Golden Rice - II (20 times more provitamin A)
and GM potatoes recently developed
• Third generation Golden Rice using indica rice being
tested (japonica variety used in other iterations
unpalatable, produced much less vitamin A)
• GE soybeans with omega-3 fatty acids (fish oil) in final
stages of FDA approval (2010)
Lowering production costs
A major advantage claimed for producing drugs through plant
biopharming is lower production costs for pharmaceuticals.
Current production methods (fermentation and cell cultures) are
characterised as inefficient, expensive and time-consuming
processes, while biopharming promises significantly lower
infrastructure and operating costs (Elbehri 2005).
Capacity shortage and flexible supply
The increased demand for protein-based drugs; manufacturing
capacity is said to be a major constraint on future supply (Elbehri
2005; Nevitt et al. 2006; Fernandez et al. 2002). According to
Nevitt et al. (2006: 104), “demand for affordable protein-based
therapies has already outpaced production capacity”, and this
pressure on capacity is expected to increase.
Advantage
Potential for new and better drugs
biopharming is its potential to produce biopharmaceuticals that cannot be
produced in other ways (Thiel 2004). Dyck et al. (2003: 395) note
problems with other production platforms (bacteria, yeast, and insect,
metazoan and mammalian cells) and suggest that transgenic plants (and
animals) may avoid these problems, thus presumably enabling successful
production of drugs that could not (or would not) otherwise be produced.
According to Ma et al. (2005).
Opportunities for patent-enhancing and patent-busting
producing new medicines, biopharming may be seen instead as a way to
undermine or reinforce patents on existing medicines. Biopharming may
enable companies to “bust” the existing patents of other companies by
developing a new process to produce a substance whose patent is
associated with another method of production. Conversely, biopharming
may enable a company to extend patent protection for a drug by acquiring
a new patent for it based on a new production method.
Conti..
Risks, Concerns and Issues
Potential gene flow to weeds or related crops through
pollination or seed contamination (horn et al., 2004).
Pdms accidentally entering the food chain and being
consumed by non-target organisms (breyer et al., 2012).
A major concern for many developing countries is the lack
of bio-safety legislation for genetically modified plants
(salehi, 2012).
Health and Environmental Risks of GE Foods
• Allergies and toxicities from new proteins entering the food supply• Eosinophilia Myalgia Syndrome from Showa Denko’s GE-L-tryptophan
supplements in 1980s
FDA covered up• Bt corn increases sensitivity of mammals to other allergens, increases
levels of cytokines and interleukins involved in various autoimmune diseases
• Bt corn toxic to caddisflies, a food resource for fish and amphibians
• Bt toxin can affect bee learning, may contribute to colony collapse disorder
• Bt found in blood of 69% of non-pregnant women, 93% of pregnant women, and 80% of fetuses
• GM peas (with bean gene) cause lung inflammation in mice – trial stopped
• New, allergenic proteins in GE soy in South Korea
Secret Monsanto report found that rats fed a diet rich in GM cornhad smaller kidneys and unusually high white blood cell counts
Monsanto’s MON 863 YieldGard Rootworm (GM) Maize damagesrats’ livers and kidneys
-Bt eggplant shows similar damage
Russian Academy of Sciences report found up to six-fold increasein death and severe underweight in infants of mothers fed GM soy
Austrian study shows impaired fertility in mice fed GM maize
Bt-cotton reported to cause skin and respiratory illnesses/allergiesin workers in Philippines
Altered nutritional value of foodstuffs
Transfer of antibiotic resistance genes into intestinal bacteria or other organisms, contributing to antibiotic resistance in human pathogens
Horizontal gene transfer of gene inserted into GM soy to DNA of human gut bacteria-Soy allergies increased by 50% after introduction of GM soy into the UK
Allergenicity in India
In India, hundreds of laborers picking cotton and working in cotton ginning
factories developed allergic reactions when handling the BT cotton. This didn’t
happen with the non-Bt varieties. [Ashish Gupta et. al., “Impact of Bt Cotton on
Farmers’ Health (in Barwani and Dhar District of Madhya Pradesh),”
Investigation Report, Oct–Dec 2005]
Hospital records: “ Show that victims of itching have increased massively this
year, and all of them are related to BT cotton farming.” [The Sunday Indian,
10/26/08]
Itching all over the body,
eruptions, wounds,
discoloration
• Pests now becoming resistant to Bt
• Meta-analysis of Bt corn and cotton (2013):
• 5/13 major pests resistant (compared with 1 in 2005)
• Bt cotton destroyed by mealy bug; harvests in India
decline dramatically, contributing to suicides among
farmers
Animal data suggest DNA can be taken up intact bylymphocytes through Peyer’s patches of small intestine
Animal studies show adverse effects on multiple organs,including tumors, multiple organ damage, and prematuredeath
Micro RNA and short interfering RNA not destroyed duringdigestion, absorbed, can affect gene expression in animalsand humans
Herbicide resistance improved crop Weeds related to crop(Same Spp)
Resistance gene transfer to weeds
Super weeds
Can’t destroy using weedicide
Pollination
X
Genetic transfer to Non target species
Super weeds ?
Super Pest ?
ReferencesBreyer, D, De Schrin, Gossens, M., Pauwels, K., Heeman, P. (2012) Biosafety of
molecular farming in GM plants. Springer. 259-274.
Franken, E., Teuschel, U. And Hain, R. (1997) Recombinant Proteins from trangenicplants. Curr. Opin. Biotech. Vol. 7 : 171-181.
Horn, M. E., Woodard, S. L and Howard J. A (2004). Plant molecular farming: systemsand products. Plant Cell. Rep. Vol. 22: 711-720.
Jelaska S, Mihaljeric S and Bauer N. (2005). Production of biopharmaceuticals,antibodies and edible vaccines in transgenic plants. Current studies of biotechnology.Vol. 4.
Mason H. S., and Arntzen, C. J. (1995). Transgenic plants as vaccine production systems. Trends Biotechnol. Vol. 13. 388-392.
Mason H. S., Lam D. M. K., and Arntzen C. J. (1992). Expression of Hepatitis B surface antigen in transgenic plants. Proc. Wall. Acad. Sci. USA. Vol. 89, 11747-11749.
Neeraj M., Prem N. G., Kapil K, Amit K. G., and Suresh P. V., (2008). Edible vaccines: A new approach to oral immunization. Ind. Jor. Of Biotech. Vol. 7. 283-294.
Rishi A. S, Nelson N. D, Goyal A. (2001) Molecular Farming in plants: A current perspective. Journal of plant biotechnology and biochemistry. Vol. 10(1). p. 1-12.
Salehi J. G., (2012) Risk assessment of GM crops; regulation and science. Boisafety. 113.