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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5690_Библиотеки_им_академика_М_И_Перельмана
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368 P. Patel et al.
Fig. 20.2 Process of plant molecular farming
20.12 History of Molecular Farming (Fig. 20.3)
2012-Plant made vaccine
Approved for human use
2006-Plant made vaccine
Approved by USDA
1998-First clinical trial
of plant derived
Pharmaceutical protein
2003-Commercialization
Trypsin-maize
1986-First plant derived
protein rhGH in tobacco
1989-First plant
Made antibody lgG1
In tobacco
1995-Oral
Vaccine potato
2006-Firsts
Commercialization of
Plant made antibody
MOLECULAR
FARMING
MILESTONE
History of molecular farming
Fig. 20.3 Molecular farming history
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20 Molecular Farming of Medicinal Plants in Face of Environmental Challenges 369
20.13 Metabolomics and Metabolite Engineering
Plants can modify their biosynthetic pathways to increase flow toward specific
desired metabolites through a process known as met abolic engineering. It tries to
create an excessive amount of a desired chemical, less of an undesirable component,
and a unique compound (one that occurs naturally but is not produced by the host
plant). Increasing flux to the target molecule, reducing flux through a competing
pathway, overcoming rate-limiting steps, overexpressing regulatory genes or tran-
scription factors to induce the pathway, or inhibiting or limiting the molecule’s
catabolism are all possible methods for increasing the level of a valuable target
molecule. Common strategies include the screening and selection of high-producing
cell lines as well as the optimization of growth production media. The foundation of
metabolic engineering is the integration of genes encoding enzymes for a specific
plant biosynthetic pathway between the Ri plasmid’s T-borders, followed by the
introduction of this construct into the plant genome. Such a method was successfully
used to increase the production of alkaloids, first in the hairy roots of C. roseus and
then in the hairy roots of different Solanaceae. A class of active diterpenes known as
tanshinone is frequently utilized to treat cardiovascular disorders. Agrobacterium-
mediated gene transfer technique was used to introduce genes for 3-hydroxy-3-
methylglutaryl CoA reductase (HMGR), geranylgeranyl diphosphate synthase
(GGPPS), and 1-deoxy-dxylulose-5-phosphate synthase (DXS) into Salvi a
miltiorrhiza hairy roots.
20.14 Technology for Hairy Root Culture
Many MAPs have undergone genetic modification to produce hairy roots. Hairy
roots of many medicinal plant species have been grown in bioreactors for secondary
metabolite de novo synthesis as well as better production. Manufacturing of high-
value metabolites and phytoremediation, biotransformation, regeneration of entire
plants, and production of synthetic seeds are some of the other key uses of modified
root cultures.
20.15 Production of Pharmaceutical Compounds and Their
Prospective Applications
Over the past 20 years, there has been a significant change in the pharmaceutical
industry’s perception of therapeutic plants and natural goods. This is because both
the general people and the scientific community have a greater understanding of and
interest in medicinal plants and herbal treatments. A review of the literature suggests
that more than 1000 businesses produce herbal products, with annual sales exceed-
ing US $60 billion. With less than 2% of the worldwide market, India ranks third in
the herbal medicine category.
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370 P. Patel et al.
The Indian market is expanding by $150 million or 15–20% annually, or Rs. 7000
million. There are numerous medicinal plants that create compounds used in
pharmaceuticals, such as secondary metabolites, for socioeconomic reasons. As an
example, the following medicinal plants are listed below, some of which are
threatened species: Adhatoda beddomei, Aristolochia spp., Aegle marmelos, Arte-
misia spp., Azadirachta indica, Bacopa monnieri, Acorus calamus, Chlorophytum
borivilianum, Boswellia serrata, Commiphora wightii, C. fantastica, Calligonum
polygonoides, Catharanthus roseus, Centella asiatica, Caralluma sp., Coptis teeta,
Coleus forskohlii, Dioscorea sp., Glycyrrhiza glabra, Ceropegia bulbosa,
Simmondsia chinensis, Gymnema sylvestre, Nepenthes khasiana species, Mentha
species, Panax species, Phyllanthus species, Plantago zeylanica, Papaver
somniferum species., Podophyllum hexandrum, Spilanthes acmella, Rhodiola
rosea, Tecomella undulata, Tribulus terrestris, Terminalia arjuna, Tylophora
indica, Vitex species, Withania somnifera species, etc.
20.16 Production of Plant-Derived Antibodies
Monoclonal antibodies, which are sizable, metameric glycoproteins that bind selec-
tively to their respective antigens and are used to cure diseases, are the most
advanced effort for human application of recombinant plant protein (Frigerio et al.
2000). Demand on the market is growing, which puts pressure on manufacturers of
antibodies to find more affordable options. Transgenic tobacco was used for the first
time to successfully assemble and express secretory immunoglobulin A in 1998
(Ma et al.
1995; Ma et al. 1998). Six different plant-derived monoclonal antibodies
are currently being tested in clinical trials: CaroRx (phase II) for the prevention of
dental caries (made in transgenic tobacco, designed to block the adherence of the
bacteria that cause cavities); various single-chain Fv antibody fragments produced
by viral vectors in tobacco against non-Hodgkin’s IgG (ICAM1) for the prevention
of the common cold, an antibody against cancer (phase II), an d Rhino RX for the
treatment of respiratory syncytial disease. Cuba recently approved the large-scale
manufacture of plant-made antibodies using an anti-hepatitis B surface antigen
antibody (Pujol et al. 2005) (Table 20.2, Fig. 20.4).
20.17 Plant-Derived Human and Animal Vaccines
for Immunotherapy
A vaccination is a biological treatment that boosts immunity to a specific disease. To
create an edible vaccine, selected desired genes are introduced into plants, and these
changed plants are then made to produce the altered protein. A streptococcus surface
protein expressed in tobacco leaves served as the first edible vaccination. There are
currently several human or animal diseases for which edible vaccines are being
developed. Let your food be your medicine, as Hippocrates advised. Vaccines made
from edible plant materials include fruits, seeds, and root vegetables. The most
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Promoter Signal sequences Plants
20 Molecular Farming of Medicinal Plants in Face of Environmental Challenges 371
Table 20.2 Medicinal plant-derived antibodies
Antibody
name or
type
Application and
specificity
Dental caries;
streptococcal
antigen I or II
CaMV 35S Murine IgG
signal peptides
Guy’s
13 (SIgA)
Nicotiana tabacum
Diagnostic; anti-
human IgG
CaMV 35S Murine IgG
signal peptides
C5-1
(IgG)
Alfalfa
Cancer treatment;
carcinoembryonic
antigen
Enhanced
CaMV 35S
TMV Ωleader;
murine IgG
signal peptides;
KDEL
T84.66
(IgG)
Nicotiana tabacum
(transiently with
Agrobacterium
infiltration)
B cell Lymphoma
treatment;
idiotype vaccine
TMV
subgenomic
coat protein
promoter
Rice α-amylase 38C13
(scFv)
Nicotiana
benthamiana
Colon cancer;
surface antigen
TMV
subgenomic
promoter
U5
CP
Murine IgG
signal peptide;
KDEL
CO17-1A
(IgG)
Nicotiana
benthamiana
Fig. 20.4 Recombinant
proteins expressed in plant
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significant benefit of oral vaccination with plant-made antigens is the transmission of
both mucosal (IgA) and systemic (IgG) protection. Animals or humans can get plant-
based antigens without processing or purification. Transgenic plants are the best
choice for creating oral vaccinations because the plant cell wall shields the antigenic
proteins from the stomach’s acidic environment, allowing them to enter the
gut-associated lymphoid tissue. The main goal of resea
rch on plant-derived vaccines
is to demonstrate their parity with currently used conventional vaccine
manufacturing techniques (Ma et al.
2005) (Figs. 20.5 and 20.6; Table 20.3).
372 P. Patel et al.
Fig. 20.5 Need of edible vaccines instead of conventional vaccine
Fig. 20.6 Process for formation of edible vaccine
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Plant
20 Molecular Farming of Medicinal Plants in Face of Environmental Challenges 373
Table 20.3 Plant-derived targeted vaccine and their action
Source of the protein
and target species for
the vaccine
Peptide or
protein
expressed
Integrity, protective capacity and
immunogenicity of the vaccine
Enterotoxigenic
E. coli (humans)
Heat labile
toxin
B-subunit
Tobacco When taken orally, intact protein
creates multimers and induces an
immune response
Hepatitis B virus
(humans)
Envelope
surface
protein
Tobacco When delivered by injection, virus-
like particles develop, and the protein
that was extracted is immunogenic
Hepatitis B virus
(humans)
Envelope
surface
protein
Lupin
(
Lupinus
spp.)
Orally given immunogenic
Norwalk virus
(humans)
Capsid
protein
Tobacco When ingested, intact protein and
virus-like particles develop and are
immunogenic
Human cytomegalic
virus (humans)
Glycoprotein
B
Tobacco Immunologically related protein
Foot-and-mouth
disease virus
(domestic animals)
VP1 Arabidopsis When given by injection,
immunogenic and protective
Foot-and-mouth
disease virus
(domestic animals)
VP1 Alfalfa When given by injection,
immunogenic and protective or by
orally
Transmissible
gastroenteritis
coronavirus (pigs)
Glycoprotein
S
Arabidopsis When delivered via injection,
immunogenic
Transmissible
gastroenteritis
coronavirus (pigs)
Glycoprotein
S
Tobacco Intact protein and immunogenic when
administered by injection
20.18 Pharmaceutical and Nutraceutical Protein Production
The first reported pharmaceutical protein made in plants was tobacco callus
expressing human growth hormone (Barta et al. 1986). Tobacco plants, genetically
modified to produce interleukin, an enzyme used in treatments for disease (e.g.,
Crohn’s disea se), are being tested in field trials in Canada by the Southern Crop
Protection and Food Research Centre (Einsiedel and Medlock 2005). Phase II
clinical trials are being conducted for gastric lipase; an enzyme derived from
transgenic corn that is used to treat cystic fibrosis (Meristem Therapeutics, France).
Phase II clinical trials for human intrinsic factor, a treatment for vitamin B12
insufficiency that is made in transgenic Arabidopsis thaliana plants, have begun
(Cobento Biotech, Denmark) (Horn et al.
2004). Both alpha-galactosidase for the
treatment of Fabry disease produced in transgenic tobacco (Planet Biotech, USA)
and lactoferrin, a functional food ingredient made from transgenic corn and utilized
as a dietary supplement (Meristem Therapeutics, France), have reached the phase I
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trial stage. Enterotoxin B produced in transgenic corn (ProdiGene, USA) and potato
(Arizona State University, USA) and aprotinin have reached the phase I trial stage in
terms of other pharmaceutical proteins. SemBioSys (Canada), Ventria (United
States), and Chlorogen (United States) are among the companies developing addi-
tional human products. SemBioSys is working on a technique for producing human
insulin in plants, while Ventria is utilizing rice to create ped
iatric dysentery
treatments, and Chlorogen is experimenting with tobacco to create pharmaceuticals
in plants for ovarian cancer. Recently, a blood clot dissolver produced in duckweed
(Biolex, United States) has entered phase I clinical trials, and an apolipoprotein
expressed in safflower (SemBioSys, Canada) to be used against cardiovascular
diseases is expected to enter clinical trials in 2008. The formation of polyunsaturated
fatty acids, the creation of human m
ilk proteins in transgenic plants, and the
production of microbicide in transgenic plants have all been patented as prospective
molecular farming products based on the scientific data that was available in 2005
and 2006.
374 P. Patel et al.
20.19 Industrial Enzymes and Other Molecules for Industrial Use
Artemisia annua is a more valuable medicinal plant which cures lots of diseases such
as malaria because of its antimalarial property, as an immunosuppressive property,
anticancerous, anti-inflammatory, and so on. In Artemisia it is mainly functional
when higher level of flavonoid content is present. These contents were increased
through metabolic engineering. A transgenic plant Artemisia annua contains
AaWRKY1 gene. This shows genetic manipulation approaches which improve the
secondary metabolite content in A. annua and the flavonoid biosynthesis pathway.
Plant molecular farming has facilitated the development of non-pharmaceutical
items, accelerating their time to market. There are 11 plant-derived proteins that
have been created and put on the market: trypsin, aprotinin, avidin, lactoferrin,
thyroid-stimulating hormone receptor, lysozyme, Hantaan and Puumala viral
antigens, peroxidase, beta-glucuronidase, cellulase, and laccase. TrypZean, a recom-
binant bovine sequence trypsin expressed in corn (ProdiGene), was the first com-
mercially available protein product in the business (Horn et al.
2004). Trypsin has a
variety of commercial uses, including the production of vaccines. It is also exten-
sively used in the detergent and leather industries (Hood et al.
2003). Historically,
this protein has been isolated and purified from bovine or porcine pancreas; how-
ever, this practice has come under increasing scrutiny due to concern s about bovine
spongiform encephalopathy (Woodard et al. 2003
). Peroxidase and laccase are
fungal enzymes largely consumed in the paper industry, and the encoding genes
have been expressed in maize (Applied Biotechnology Institute, United States). The
production of biofuel from plants has grown in significance with rising oil costs. The
most prevalent biopolymer found in plant cell walls is cellulose, which is made up of
lengthy chains of glucose molecules. These chains are hydrolyzed by the cellulase
enzyme into glucose monomers, which can then be fermented by microbes to
produce ethanol. Recently, genes expressing fungal cellulase have been expressed
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Host plant Protein
in corn to produce large quantities of this enzyme (Applied Biotechnology Institute,
United States) (Table 20.4).
20 Molecular Farming of Medicinal Plants in Face of Environmental Challenges 375
Table 20.4 Application of potential protein on host plant
Potential application or
indication
Human protein
Anticoagulant Tobacco Human protein C
Neutropenia Tobacco Human granulocyte-macrophage colony-
stimulating factor
Growth hormone Tobacco
Tobacco
Human somatotropin, chloroplast
Nuclear expression
Anemia Tobacco Human erythropoietin
Antihyperalgesic by opiate
activity
Arabidopsis Human enkephalins
Wound repair and control of cell
proliferation
Tobacco Human epidermal growth
Hepatitis C and B treatment Tobacco Human interferon β
Liver cirrhosis, burns, surgery Tobacco Human serum albumin
Blood substitute Tobacco Human hemoglobin α, β
Collagen Tobacco Human homotrimer collagen
Non-human protein
Hypertension Tobacco Angiotensin-converting enzyme
HIV therapies Nicotiana
benthamiana
Α-Trichosanthin from TMV-U1
subgenomic
coat protein
Gaucher’s disease Tobacco Glucocerebrosidase
20.20 Human Proteins and Biopharmaceuticals Generated from
Plants
Pharmaceutical proteins generated in transgenic plants have typically been produced
at quantities lower than the 1% of total soluble protein required for commercial
viability if the protein needs to be purified. In a modest human investigation, plant-
derived recombinant hepatitis-B surface antigen generated only a minimal serum
antibody response, perhaps due to the transgenic lettuce’s low expression level
(1–5 ng g1 fresh weight). Despite recent advancements in potato expression levels
for clinical trials31, expression levels need to be raised even more for usable
purposes. Furthermore, the expression levels of the Norwalk virus capsid protein
(0.37% of total soluble protein) are too low for widespread oral administration, even
though eating potatoes caused oral immunization. Human serum albumin, 0.001%
total soluble protein; protein C, 0.001% total soluble protein; erythropoietin, 0.003%
total soluble protein; and human interferon, 0.001% fresh weight – these additional
human proteins – have been disappointingly under-expressed in transgenic plants.
Only 0.001% of the total soluble protein in transgenic tobacco was expressed by a
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synthetic gene that codes for human epidermal growth factor. Even though there
have been several successful reports of non-human proteins (such as phytase and
glucanase) being expressed at high levels via the nuclear genome, there is still a
significant need to boost the expression of human blood proteins in order to enable
the industrial production of proteins that are crucial for pharmacology in plants.
376 P. Patel et al.
20.21 Conclusion
Recombinant proteins with therapeutic value can be produced in plants effectively
and efficiently. There are several different plant species being investigated for use as
green bioreactors, each with unique benefits and drawbacks. In comparison to
transgenic animals, transgenic plants exhibit low manufacturing costs, high produc-
tivity, no risk of contamination, and simple storage. As a result, it offers an alterna-
tive to traditional fermentation systems that rely on bacteria, yeast, or mammalian
cells. In a variety of disease models, including hepatitis B, rabies, etc., PMPs have
already attained preclinical confirmation.
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