Tobacco shoot regeneration from calli in temporary immersion culture for biosynthesis of heterologous biopharmaceuticals Sherwin Savio Barretto Thesis submitted for the Degree of Doctor of Philosophy PhD Imperial College London Department of Life Sciences Faculty of Natural Sciences Imperial College London 2014
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Tobacco shoot regeneration from calli in temporary
immersion culture for biosynthesis of heterologous
biopharmaceuticals
Sherwin Savio Barretto
Thesis submitted for the Degree of Doctor of Philosophy PhD
Imperial College London
Department of Life Sciences
Faculty of Natural Sciences
Imperial College London
2014
1
Declaration of Originality
I hereby declare that this thesis, submitted in fulfilment of the requirements for the degree of
Doctor of Philosophy of Imperial College London, represents my own work and has not been
previously submitted to this or any other institute for any degree, diploma or other
qualification.
Sherwin Savio Barretto
2
Copyright Declaration
The copyright of this thesis rests with the author and is made available under a Creative
Commons Attribution Non-Commercial No Derivatives licence. Researchers are free to copy,
distribute or transmit the thesis on the condition that they attribute it, that they do not use it
for commercial purposes and that they do not alter, transform or build upon it. For any reuse
or redistribution, researchers must make clear to others the licence terms of this work.
3
Abstract
‘Molecular farming’, the use of transgenic plants to produce biopharmaceutical proteins is
emerging as a new biotechnological paradigm. Transgenic plants offer several advantages
over conventional microbial and mammalian cell host technologies. In particular,
transplastomic plants, with transformed plastid genomes, are capable of massive expression
of foreign proteins and represent a promising platform for biopharmaceutical synthesis.
The main theme of this PhD thesis is the investigation of in vitro regeneration of tobacco
(Nicotiana tabacum) shoots from callus tissue in temporary immersion (TI) culture for
heterologous biopharmaceutical synthesis. There is special emphasis on subunit vaccine
expression in transplastomic tobacco, in which foreign protein accumulation is correlated
with chloroplast number and development during the organogenesis process.
Studies using transplastomic N. tabacum expressing TetC (tetanus toxin fragment C)
investigated the influence of several culture parameters on biomass regeneration and
recombinant protein expression. The parameters investigated include medium nitrogen source
ratio, sucrose concentration and hydrodynamics. These studies highlight the sensitivity of
transplastomic protein yields to the culture microenvironment, and provide a starting point
for further optimisation. Further studies demonstrated the feasibility of TI culture for
biosynthesis of proteolytically-unstable transplastomic subunit vaccines, p24 (HIV antigen)
and VP6 (rotavirus antigen). TI culture is also demonstrated as a means for nuclear
expression of functional Guy’s 13 monoclonal antibody. Finally, the use of TI culture as the
basis of novel technological innovations is investigated. This includes the demonstration of
transplastomic protein expression in a prototype large-scale mechanical temporary immersion
bioreactor. Encapsulation of callus aggregates in an alginate matrix for long-term germplasm
preservation was trialled, prior to temporary immersion regeneration.
Overall, this work presents a novel in vitro propagation method for the contained large-scale
biosynthesis of biopharmaceutical proteins, as a potential alternative to conventional plant
propagation platforms based on agricultural cultivation or cell suspension culture.
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Acknowledgements
I gratefully acknowledge all the individuals who have provided the assistance and support I
needed to complete this complex assignment.
First of all, I would like to express my sincere gratitude and deep appreciation to my
supervisor, Prof. Peter Nixon, for providing me with the opportunity to pursue this exciting
and challenging PhD project, and for all his guidance and support. I am equally grateful to
my co-supervisor Prof. Klaus Hellgardt whose guidance and invaluable technical ‘know-
how’ has helped me tremendously. I would like to give my deepest thanks to Dr Franck
Michoux, the post-doc who started this project and who in many ways has acted as my
‘unofficial supervisor’. I am extremely grateful for his assistance, support, time and patience.
I would like to thank all members of the 7th floor of the Ernst Chain Building, past and
present, for their cooperation, encouragement, support and friendship. I would especially like
to thank Hussain Haji Taha, Dr Jianfeng Yu, Shengxi Shao, Dr Niaz Ahmad, Dr Steven
Burgess, Dr Marko Boehm, Dr Charlotte Ward, Dr Agripina Banda, Sana Asghar, Xu Zhao,
Alexandros Papagiannakis, Jiyao Gan, Chi Zeng, Zheng-Yi Wei, Jayasudha Nagarajan,
Marin Sawa, Charlie Cotton, Jeffery Douglass, Sven Dc, Dr Tanai Cardona Londono, Dr
Karim Maghlaoui, Dr Alison Telfer, Katharina Brinkert, Dr Wojciech Bialek, Dr Andreas
Fantuzzi, Dr Gillian Young, Ruiqiong An, Dr Masooma Rasheed, Ewelina Krysztofinska,
Mostafa Jamshidiha, Dr Lisa Hale, Dr Justin Yeoman, Dr James MacDonald, Bhavish Patel,
Dr Christian Richard, Amanda Koslovaite and all other lab-fellows, past and present, whom I
have had the greatest pleasure crossing paths with. In particular, I will always remember Prof.
Bill Rutherford for his carefree attitude, advice and chats.
I would like to thank all my collaborators, for their help, guidance, materials and equipment. I
would like to thank Prof. John Gray, University of Cambridge for providing me with the
transplastomic seeds for the expression of p24 and VP6 and the accompanying antibodies. I
would like to thank Prof. Julian Ma and Pascal Drake for providing me with the transformant
seeds for the expression of Guy’s 13 monoclonal antibody. These collaborative efforts have
helped in the advancement of the scientific endeavour.
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I would like to thank the Biotechnology and Biological Sciences Research Council (BBSRC)
Targeted Priority Studentships initiative for funding this work.
I am deeply indebted to my family for their love, support, encouragement and prayers for my
success.
Finally, I would like to give thanks to Almighty God, for the innumerable graces and
blessings bestowed upon me to enable me to undertake this pursuit.
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Table of Contents
Table of Contents .................................................................................................................................... 6
List of Figures ........................................................................................................................................ 14
List of Tables ......................................................................................................................................... 17
List of Abbreviations ............................................................................................................................. 18
Figure 1.1 Technological design and operational principle of Twin‐Flask system .............................. 35
Figure 1.2 Technological design and operational principle of RITA® system ..................................... 36
Figure 1.3 Technological design and operational principle of bioreactor of immersion by bubbles
system ................................................................................................................................................. 36
Figure 1.4 Downstream processing routes for seed and leaf crops ................................................... 38
Figure 1.5 Gene map of plastid genome from tobacco (N. tabacum). ............................................... 41
Figure 1.6 Schematic representation of the chloroplast expression cassette .................................... 46
Figure 2.1 Operation of large-scale mechanical bioreactor ............................................................... 60
Figure 3.1 Callus-meristemoid transition and shoot bud formation. ................................................. 71
Figure 3.2 Logistic increase of fresh and dry biomass accumulation during in vitro organogenesis in
6.2.3.2 Influence of Influence of duration and temperature of encapsulated callus
preservation on TetC expression in regenerated shoots
SDS-PAGE and immunoblot analysis was undertaken to assess the influence, if any, of callus
encapsulation duration and temperature on TetC intrinsic yield (Figure 5.10). No significant
differences were observed between the various treatments. The TetC intrinsic yields under all
storage durations and temperatures are comparable to that in biomass grown in the control
culture (inoculum was not encapsulated).
6.2.3.3 Discussion on the influence of alginate encapsulation on temporary
immersion regeneration and TetC expression
With alginate encapsulation for callus preservation, there is a trade-off in terms of the gradual
loss of regeneration potential with increased germplasm storage time, which is heightened at
room temperature compared to 4°C, as these results have shown. This is due to reduced
Figure 6.10 SDS-PAGE and
immunoblot demonstrating
TetC expression in shoot
biomass regenerated from
encapsulated callus stored for
various durations and
temperatures. TetC control
culture was inoculated with non-
encapsulated callus. Negative
control is TIB-grown WT biomass.
12% acrylamide; LWM marker
(A); Precision Plus marker (B); 8
µg protein loading per well; Sypro
orange staining.
156
viability of callus germplasm with prolonged storage. However, alginate encapsulation may
still be useful as a viable method for short-term germplasm preservation, in spite of reduced
growth potential. For example, 40 days alginate preservation of callus at 4°C will result in
fresh biomass accumulation of 178.6 g l-1, compared to 277.8 g l-1 if no storage was
undertaken. Although this represents a 36% loss in fresh weight, the 40-day decoupling of
inoculum generation and biopharmaceutical manufacture may be invaluable in satisfying
unpredicted increases in demand. This reduction in growth potential of encapsulated
germplasm with increased storage time is consistent with previous studies (Naik and Chand,
2006; Perveen and Anis, 2014; Rai et al., 2008; Zych et al., 2005).
6.3 Discussion on described studies and how they relate to new
developments in in vitro molecular farming
These studies have highlighted two areas of intense research and innovation in the
micropropagation field, the development of large-scale cell and tissue culture capabilities,
and the preservation of germplasm. (Dodds, 1988; George et al., 2007; Murashige, 1977;
Patel et al., 2000). Such developments in micropropagative technology can be easily adapted
to the high throughput biosynthesis of plant-produced biopharmaceuticals.
The first study focussed on the development of a large-scale hydraulically-driven temporary
immersion bioreactor for the biosynthesis of transplastomic vaccines. Although there has
been notable progress in the development and scale-up of plant cell suspension cultures for
recombinant protein and small molecule synthesis over the last 30 years (Boivin et al., 2010;
Eibl and Eibl, 2008; Kieran et al., 1997; Kwok et al., 1992; Magy et al., 2014; Moon et al.,
1999; Scragg et al., 1988; Srinivasan et al., 1995; Terrier et al., 2007), there has been little
equivalent innovation in large-scale culture of differentiated plant tissues (Huang and
McDonald, 2012; Steingroewer et al., 2013). Most projects involving recombinant protein
expression in whole tissues have focussed on field or greenhouse seedling propagation
(Artsaenko et al., 1998; Busse et al., 2002; Ko and Koprowski, 2005), although as an
exception, there has been moderate progress in the development of systems for culturing
hairy roots / rhizosecretion (Drake et al., 2003; Drake et al., 2009; Wongsamuth and Doran,
1997) and mosses (Decker and Reski, 2004; Decker and Reski, 2007; Hohe and Reski, 2002).
It is likely that in the near future, tissue culture scale-up will become an intense field of
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research, as the need for high-throughput in vitro differentiated biomass growth systems for
biopharmaceutical synthesis will increase. This is especially relevant for transplastomic
protein expression, which is highly dependent on the development of mature chloroplasts in
differentiated leafy tissue. This study demonstrates a very straightforward strategy for the
scale-up of temporary immersion culture, which provides transplastomic protein yields
comparable to that in 0.5 l RITA cultures. Such a system does not require sophisticated
equipment, instrumentation or ‘stainless steel’ infrastructure associated with microbial
fermentation plants and is amenable to a disposable single-use bioprocessing approach (Eibl
et al., 2010; Huang and McDonald, 2012; Kwon et al., 2013). Single-use approaches confer
technical benefits relating to simplified bioprocess set-up such as ease of validation, less
capital investment for stainless steel vessels, reduced turnover time between each run, and the
potential use of integrated processes for more robust processes with shorter development time
and increased throughput (Eibl et al., 2010; Huang and McDonald, 2012).
The short-term to mid-term preservation of germplasm is an important part of any in vitro
micropropagation programme. Cryopreservation and alginate encapsulation are two
important methods for preservation of elite plant lines in commercial micropropagation and
plant conservation, though the latter is the simpler and cost-effective option (Perveen and
Anis, 2014). Hence alginate encapsulation protocols for vegetative propagules have been
established for a number of woody and non-woody species (Gardi et al., 1999; Hung and
Trueman, 2012; Kim and Park, 2002; Nagamori et al., 1999; Perveen and Anis, 2014). In
terms of in vitro tissue culture for biopharmaceutical production, preservation of germplasm
may confer several technical benefits. Alginate encapsulation may be employed in the
banking of stable transformant lines, after genetic stability has been established. Alginate
encapsulation can be used in the maintenance of a stable inventory of germplasm. Hence,
when demand for a biotherapeutic peaks, a source of tissue culture inoculum is readily
available to scale-up biosynthesis to satisfy demand. In practical terms, encapsulated
propagules may be easily transported between labs and culture facilities with minimal loss of
viability.
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Chapter 7 Summary and future directions
7.1 In vitro plant tissue culture as an alternative platform for
biosynthesis of biopharmaceuticals
The ‘molecular farming’ paradigm started in the early 1980s, when the first successful higher
plant transformation was reported, (Fraley et al., 1983), soon followed by the earliest reports
of expression of antibodies in plants (During, 1988; Hiatt et al., 1989). Since then, an intense
global programme of research and development into plants as suitable hosts for foreign
protein expression has been underway (Faye and Gomord, 2010; Ritala et al., 2014;
Schillberg et al., 2013; Spök et al., 2008a; Xu et al., 2012b). However, despite the
demonstrated advantages over conventional host technologies (Xu et al., 2012b), 30 years
later, only a small number of plant-produced therapeutics have been licensed, notably a
poultry vaccine against Newcastle disease (though this was never marketed) (Dow
Agrosciences, USA) (Katsnelson et al., 2006; Ritala et al., 2014), ELELYSO™ enzyme
replacement therapy for Gaucher disease (Protalix BioTherapeutics, Israel, in collaboration
with Pfizer) (Zimran et al., 2011) and ZMapp monoclonal antibody treatment against Ebola
(Qiu et al., 2014). A number of reasons behind the apparent decoupling of research and
commercialisation of plant-made biopharmaceuticals have been cited, including low initial
yields of foreign proteins, recalcitrance of industry leaders to replace firmly-established
microbial or mammalian bioprocesses with plant-based platforms, biosafety concerns related
to open field cultivation, and regulatory frameworks tailored to non-plant host systems
(Fischer et al., 2013; Martine et al., 2009; Soria-Guerra et al., 2011; Spök et al., 2008a; Spök
et al., 2008b; Xu et al., 2012b; Xu et al., 2011). It must be remembered that many of these
apparent bottlenecks hampering the adoption of molecular farming approaches are directly
related to the host tissue and cultivation method (Doran, 2013).
Historically, conventional soil-based cultivation of whole plants has been implicated as being
pertinent for the high-yield production of plant-made pharmaceuticals, as standard
agricultural procedures represent a very straightforward, low-tech approach and field
cultivation is highly scalable (Doran, 2000; Fischer et al., 2012; Rybicki, 2009; Stoger et al.,
2002; Xu et al., 2012b). Soil cultivation is the standard and most intuitive approach to both
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leafy and seed-based biomass growth (Xu et al., 2012b). The preference for soil-grown
seedlings appears to be reflected in much of the ‘molecular farming’ research zeitgeist over
the last 30 years (Chargelegue et al., 2005; Ma et al., 1994; Villani et al., 2009). In principle,
the case for agriculturally cultivated transgenic plants is compelling, though in reality, a
number of practical issues persist. Long development times, dependence of biomass yields on
prevailing environmental (biotic and abiotic) conditions and season, and genetic variation as
a result of sexual reproduction can affect product quality and consistency in accordance with
GMP principles (Fischer et al., 2012). Moreover transformational biosafety strategies, based
on transplastomic maternal inheritance (Daniell et al., 2002), or male sterility through RNA
silencing or barnase-induced (Commandeur et al., 2003; Gleba et al., 2004), are not absolute
guarantees against transgene pollution. Indeed, recalcitrance from both the public and
regulatory bodies have hindered large-scale field cultivation of transgenic biopharmaceutical
crops, especially in the European Union (Sang et al., 2013; Spök et al., 2008a). It is hoped
that the proliferative global adoption of genetically modified food crops (also known as
‘biotech’ crops) since the 1990s, especially USA, Brazil, Argentina, India, Canada, and
China, (James, 2013) will set the precedence for a similar adoption of biopharmaceutical
crops.
The strength of in vitro plant growth compared to agricultural propagation is in the ability to
control environmental conditions. Suspension culture has been pursued as a viable alternative
to agricultural plant propagation by researchers and industrialists (Hellwig et al., 2004;
Schillberg et al., 2013; Weathers et al., 2010; Xu et al., 2011). Suspension culture combines
the benefits of whole plant systems with those of microbial or mammalian cells (Hellwig et
al., 2004; Xu et al., 2011). Dedifferentiated callus aggregates can be cultured under scalable
tightly controlled conditions in a similar manner to industrial microbial fermentations, and
the same approaches to bioprocess optimisation can be applied (Xu et al., 2011). Moreover,
suspension cultures have fewer regulatory and environmental compliance hurdles for
ensuring product quality and safety than soil-grown plants (Xu et al., 2011). This must be
balanced against considerably higher capital costs than for soil-grown plants (Weathers et al.,
2010). Cell suspension culture has a relatively long history of over 50 years, initially as a
means for commercial high-value metabolite synthesis (Georgiev et al., 2009), and in recent
years as a platform for recombinant protein expression (Hellwig et al., 2004; Holland et al.,
2010; Schillberg et al., 2013; Vasilev et al., 2013; Weathers et al., 2010). Despite decades of
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bioprocess optimisation, low recombinant protein yields are still a major limitation of cell
suspensions (Twyman et al., 2013).
While agriculturally produced whole plants have been the host system of choice for
preclinical and clinical development of plant-made biopharmaceuticals (Karg and Kallio,
2009), and cell suspension technologies are emerging as a technically superior alternative
(Xu et al., 2011), there has been relatively little development in the development and scale-up
of plant tissue and organ cultures for biopharmaceutical production (Steingroewer et al.,
2013). While micropropagation techniques for multiplication and ex vitro transfer of plantlets
have been developed and optimised for decades, these have been applied mainly to
commercial horticulture and conservation of rare plants (Akin-Idowu et al., 2009; Dubranszki
and da Silva, 2010; Escalona et al., 1999; Kumar et al., 2006; Zych et al., 2005). There has
been some precedence of in vitro differentiated plant tissue culture for synthesis of bioactive
metabolites, though this has been largely limited to hairy roots and adventitious roots
(Steingroewer et al., 2013; Weathers et al., 2010). There has been considerable investigation
of hairy root culture for synthesis of bioactive metabolites, though scaled-up and
commercially feasible technologies are currently lacking (Bourgaud et al., 2001; Choi et al.,
2006; Georgiev et al., 2008; Steingroewer et al., 2013). Adventitious roots have been
particularly successful for commercial production of several metabolites, with over 45 tonnes
fresh weight per year reported by CBN Biotech Company (South Korea) for ginseng
production (Baque et al., 2012; Steingroewer et al., 2013). Although the in vitro culture of
differentiated explants such as shoots, plantlets, bulbs, microtubers and embryos have been
undertaken in commercial micropropagation for decades (George et al., 2007), and more
recently for the synthesis of bioactive metabolites (Steingroewer et al., 2013), there are few
reports of these used for the expression of recombinant proteins. Recent studies undertaken
by the Nixon group demonstrated that in vitro shoots regenerated from callus in temporary
immersion bioreactors could result in the overexpression of transplastomic proteins,
including TetC tetanus antigen, GFP+ (Michoux et al., 2011) and Lyme disease vaccine
antigen (Michoux et al., 2013). These were the first reports of in vitro shoots regenerated in
bioreactors being used for the expression of foreign proteins and the studies presented in this
PhD dissertation follow on from these pioneering studies.
Perhaps an explanation for the limited exploitation of in vitro tissue and organ cultures for
molecular farming lies in the intrinsic features of in vitro differentiated plant tissues (Huang
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and McDonald, 2012; Steingroewer et al., 2013). Suspension cultures, being composed of
undifferentiated callus aggregates have been relatively simple to grow in accordance with
GMP principles, borrowing heavily from bioprocessing strategies of established microbial
fermentations and mammalian cell cultures (Hellwig et al., 2004; Schillberg et al., 2013;
Weathers et al., 2010; Xu et al., 2011). In contrast, tissue cultures are morphologically and
biochemically complex. Traditional bioreactor configurations used for cell suspensions such
as stirred-tank reactors are not suited to differentiated tissues, as mechanical agitation,
hydrodynamics and reduced mass transfer and oxygen supply limitations in liquid culture can
be damaging to plantlet morphology at high biomass concentrations (Huang and McDonald,
2012; Steingroewer et al., 2013; Weathers et al., 2010). However, with modifications to
design and operation of stirred tank reactors, stirred tank bioreactors may be adapted to
differentiated tissues (Steingroewer et al., 2013). For example, low impeller speeds of 30-100
min-1 are recommended and tolerable tip speeds vary between 1 and 2 m s-1 (Steingroewer et
al., 2013). It is recommended to keep power input per unit volume under 1000 W m-3 for
reduced shear damage (Steingroewer et al., 2013). Pneumatic bioreactors, such as bubble
column reactors, have simple designs and operations, and may be used to alleviate the issues
associated with mechanical agitation, though there may be mass transfer limitations at high
tissue densities, caused by gas channelling among dense organs (Choi et al., 2006;
Sivakumar, 2006; Steingroewer et al., 2013; Vlaev and Fialova, 2003; Wang and Zhong,
2007). For metabolite production in hairy root culture, ‘unorthodox’ designs such as liquid-
dispersed and gas-phase bioreactor configurations have been used to alleviate such issues
(Weathers et al., 2010). Avoidance of stress conditions related to permanent submersion,
through the use of temporary immersion micropropagation has also been applied for a variety
of explants (Watt, 2012), though research undertaken in the Nixon group represents the first
application of this for biopharmaceutical production (Michoux et al., 2013; Michoux et al.,
2011).
The studies presented in this dissertation demonstrate the feasibility of in vitro tissue culture
via temporary immersion culture as an alternative to both agricultural propagation and cell
suspension, providing the advantages of differentiated tissue cultivation with the ease of
manipulating production conditions associated with suspension culture in bioreactors. In this
system, biomass and recombinant protein yields can easily be modulated through
manipulation of various culture parameters. The temporary immersion organogenesis system
can be a viable platform for large-scale GMP production of biopharmaceuticals, in a
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technically competent and economical manner. This system is especially suitable for the
biosynthesis of transplastomic proteins, as intrinsic protein expression is approximately 15-
fold higher in differentiated shoots than callus suspension in the case of TetC, reflecting
chloroplast maturation during morphogenesis. Moreover, 500-fold fresh weight biomass
accumulation is observed in this system.
7.2 The influence of temporary immersion shoot regeneration on
biosynthesis of transplastomic proteins
Chapters 3, 5 and 6 of this PhD dissertation have focussed on the biosynthesis of
transplastomic proteins in temporary immersion culture of N. tabacum shoots. In particular,
Chapter 3 focussed on the effects of various culture parameters on yield of TetC.
In the early development of the molecular farming paradigm, low intrinsic yields of foreign
proteins rendered transgenic plants uneconomical host systems compared to established
mammalian and microbial systems, and hindered the adoption of the new technology by
industry (Sabalza et al., 2014). Currently, these low yields have been addressed a number of
genetic strategies, transplastomics for overexpression in plastids (Bock, 2007; Bock, 2014;
Clarke and Daniell, 2011; Maliga and Bock, 2011), transient expression (Boivin et al., 2010;
Davies, 2010; Joh et al., 2005), inclusion of genetic regulatory elements in transplastomic and
nuclear transformation constructs for more efficient transcription and translation (Parra et al.,
2011; Ruhlman et al., 2010; Sharma et al., 2008). Plant growth conditions are also important
in determining yields of foreign protein (Sabalza et al., 2014).
As was emphasised in Chapter 3, ‘absolute’ foreign protein yield is the multiplication of
intrinsic yield (target protein as percentage of total soluble protein or per unit biomass) by
total biomass (expressed as fresh weight or soluble protein equivalent). Both depend on the
complex interplay of several genetic, biochemical, physiological and environmental factors.
The intrinsic yield is a measure of accumulation of protein, which depends on the rate of
protein synthesis balanced against protein degradation (Sabalza et al., 2014). In vitro biomass
accumulation depends on several metabolic and physiological factors including nutrient
163
assimilation, photosynthetic capacity and cytokinin-induced morphogenesis (George et al.,
2007).
Various culture treatments and factors were found to affect transplastomic protein
accumulation (both intrinsic and absolute), to various degrees. Transplastomic protein yields
were especially sensitive to nitrogen source ratio, sucrose concentration, irradiance, MS basal
medium concentration, hydrodynamics and protease activity. Other treatments were found to
have little or no influence on transplastomic protein accumulation, including water stress-
induced hyperhydricity, medium pH, mechanical immersion (as opposed to pneumatic
immersion) and scale-up, and encapsulation of callus inocula in alginate.
It is possible that protein localisation in the chloroplast stroma may isolate the foreign protein
from certain cellular phenomena which would otherwise adversely affect protein
accumulation. For example, hyperhydricity, a predominantly apoplastic phenomenon, was
demonstrated to have no effect on TetC expression in the plastids. Encapsulation of callus in
alginate presumably had no influence on chloroplast development, and therefore did not
affect transplastomic protein expression (though it did influence the extent of shoot
regeneration). Transplastomic protein expression was enhanced at reduced sucrose
concentrations, which is directly related to elevated photosynthetic capacity and development
of chloroplast thylakoids (Arigita et al., 2002). The requirement of both nitrate and
ammonium for biomass morphogenesis and transplastomic protein expression is related to the
assimilation of nitrogen for synthesis of amino acid and proteins and nitrogen metabolism in
the chloroplasts.
The experiments investigating the influence of hydrodynamics on biomass accumulation and
transplastomic protein were particularly intriguing, with implications for scale-up of
pneumatic temporary immersion culture. This was the first reported attempt to quantify
biological responses against hydrodynamics for in vitro shoot regeneration, although similar
studies have been undertaken for plant suspension cultures (Dunlop et al., 1994;
MacLoughlin et al., 1998; Scragg et al., 1988; Sowana et al., 2001). For 40-day temporary
immersion cultures, a critical air flow rate of 440 ml min-1 was identified, corresponding to
an average shear rate of 96.7 s-1 and energy dissipation rate of 8.82 mW kg-1 and total energy
dissipation of 127 J kg-1 (over first 20 days), which resulted in significantly reduced biomass
accumulation, mitochondrial activity and transplastomic protein yields. If scale-up of
164
pneumatic temporary immersion regeneration is to be undertaken, it is recommended not to
reach these values. The steady decline in transplastomic protein intrinsic and volumetric
yields even at moderate air flow rates suggests that operating at low air flow rates is
advisable.
These studies investigating the influence of various parameters on transplastomic protein
yields can serve as “prior art” for further optimisation of culture conditions for maximisation
of protein yields. These studies involved deviations from standard culture conditions,
involving the classical approach of alteration of one parameter at a time. The limitation of
this approach is that it does not account for interactions between factors tested (Vaidya et al.,
2009). However, these studies can be the starting point for medium optimisation by
‘statistical experimental design’ techniques, such as fractional factorial design or response
surface methodology, which can give insight into synergistic effects between medium
components (Dinarvand et al., 2013; Jeon et al., 2014; Vasilev et al., 2013). A combination of
fractional factorial design and response surface methodology was applied to the optimisation
of culture medium for tobacco BY-2 cells producing a secretory antibody (Vasilev et al.,
2013).
7.3 Scale-up of callus-to-shoot regeneration for biopharmaceutical
expression
Chapter 6 of this PhD dissertation described the scale-up of temporary immersion shoot
morphogenesis for transplastomic biopharmaceutical expression in a hydraulically-driven
mechanical bioreactor, from 0.5 l (standard bench-scale RITA® culture) to 60 l (volume of
the biomass chamber, though the volume of the entire set-up was 145 l). This is the first
reported attempt of the scale-up of in vitro callus-to-shoot morphogenesis, and could be the
basis of large-scale biopharmaceutical synthesis in differentiated tissues. Importantly, it was
observed that biomass accumulation and transplastomic protein yields were comparable to
that in small-scale RITA® bioreactors.
While suspension cultures have been successfully scaled up from shake flasks to working
volumes of 50 – 100 l or greater, with little impact on growth kinetics (Terrier et al., 2007),
tissue and organ cultures are known to be difficult to scale-up (Steingroewer et al., 2013;
165
Weathers et al., 2010). This has not been a pertinent issue in commercial horticultural
micropropagation, in which multiplication of small-scale culture vessels has been common
(George et al., 2007). To date, little progress has been made in the scale-up of shoot cultures.
Shoot propagules are sensitive to shear damage and form dense clumps in which mass
transfer may be limited. Mass propagation of Stevia rebaudiana shoots to 65 kg fresh weight
were reported in a 500 l bioreactor without mechanical agitation (Akita et al., 1994;
Takayama and Akita, 1994; Takayama and Akita, 2006). More modest attempts to scale-up
micropropagation, such as producing high quality orchid plantlets in medium-scale rocker
boxes, have been reported (Adelberg, 2006; Weathers et al., 2010).
The choice of explant is also important in scale-up of tissue culture for biopharmaceutical
expression and can affect product quality and consistency. The 500 l culture of Stevia used
shoots as inocula, though this may be inadvisable for biopharmaceutical expression. Direct
organogenesis using shoots as inocula may be difficult to scale-up for a number of reasons.
Shoots have only a limited number of meristems, thereby limiting regenerative potential.
Shoots have complex morphologies, which complicates scale-up approaches as well as
handling and inoculation (Akita et al., 1994; Takayama and Akita, 1994; Takayama and
Akita, 2006). Moreover, the competence to form shoot buds can be highly variable and
depend on length of leaves (Sreedhar et al., 2008), and regenerative potential decreases with
age of leaves (Ibrahim and Debergh, 2001; Sreedhar et al., 2008). As a compromise,
primordia can be used as inocula, being more convenient for inoculation and able to form
many shoots (Akita et al., 1994; Takayama and Akita, 1994). In the studies outlined in this
PhD thesis, dedifferentiated callus was used as inocula. Callus tissue is an advisable choice of
explant for molecular farming purposes. Callus is a relatively homogeneous, unorganised
tissue with high regenerative potential, containing multiple meristemic nodes (George et al.,
2007; Ikeuchi et al., 2013), and therefore better suited to GMP production of
biopharmaceuticals.
7.4 Biosynthesis and assembly of functional monoclonal antibodies in
temporary immersion shoot regeneration
30 years of previous studies have confirmed that plants possess the relevant cellular
‘machinery’ to express, assemble and post-translationally modify antibodies with antibody-
166
binding function (Artsaenko et al., 1998; Brodzik et al., 2006; Drake et al., 2003; Drake et al.,
2009; Hiatt et al., 1989; Hiatt and Pauly, 2006; Holland et al., 2010; Khoudi et al., 1999; Ko
and Koprowski, 2005; Ko et al., 2003; Ma et al., 1998; Ma et al., 1994; Magy et al., 2014;
Qiu et al., 2014; Tavladoraki et al., 1993; Vasilev et al., 2013). However, the studies
described in Chapter 4 describe the first reported attempt to express functional monoclonal
antibodies in in vitro regenerated shoots, using expression of nuclear-encoded Guy’s 13
antibody in N. tabacum as a model system. These studies demonstrate the potential
application of temporary immersion regeneration of shoots from callus for monoclonal
antibody expression, giving antibody titres comparable to soil-grown plants. Until now,
studies involving expression of mAbs in plants have involved soil cultivation of whole plants
(Artsaenko et al., 1998; Busse et al., 2002; Ko et al., 2009; Stoger et al., 2000), although there
have been some innovations in the development of root rhizosecretion systems (Drake et al.,
2003; Drake et al., 2009) and cell suspensions (Holland et al., 2010; Vasilev et al., 2013).
Unexpectedly, hyperhydricity (vitrification) of shoots resulted in increased antibody titres,
which presents an opportunity to enhance titres through imposition of water stress.
The expression of antibodies in transgenic plants (“plantibodies”) is one of the most exciting
technological developments of the molecular farming field (Ko et al., 2009; Ko and
Koprowski, 2005). This study presents an alternative in vitro biomanufacturing platform
which is amenable to GMP standards of quality and consistency. Glycosylation, the covalent
linkage of sugar moieties to proteins, is an important post-translational modification of
immunoglobulins in mammals (Wright and Morrison, 1997). In plant cells, glycosylation
occurs in the secretory pathway in the ER and Golgi. However, the mechanisms of N-linked
glycosylation differ in plants and mammals (Schoberer and Strasser, 2011). Plants add α(1,3)
fucose and β(1,2) xylose residues to the N-glycan of their glycoproteins, whereas mammals
add α(1,6) fucose moieties, glucose and sialic acid residues to the N-glycan (Obembe et al.,
2011). Plant glycans are immunogenic in several mammals, although their role in human
allergies has not been clarified (Bardor et al., 2003; Sabalza et al., 2014; van Ree et al.,
2000). Nonetheless, the potential impact of plant glycans on immunogenicity and adverse
allergic reactions, there is a need to engineer plants to emulate human N-glycosylation
(Gomord et al., 2010; Sabalza et al., 2014). One strategy is to include the fusion of the ER-
retention signal KDEL, to ensure glycosylation is only of the universal ‘high mannose type’
(Petruccelli et al., 2006; Saint-Jore-Dupas et al., 2007; Triguero et al., 2005). Another
approach is ‘glycoengineering’, in which host plants have been engineered to prevent
167
addition of plant-type glycans or add human-type glycans (Fischer et al., 2012; Ko et al.,
2008). However, plant glycosylation can even be beneficial for enhanced antibody avidity, as
is the case of Protalix’s Gaucher’s disease therapeutic, ELELYSO™ (taliglucerase alfa), a
recombinant glucocerebrosidase produced in carrot cells (Protalix BioTherapeutics, Israel)
(Fischer et al., 2012; Sabalza et al., 2014). The glucocerebrosidase is targeted to localise in
vacuolar compartments for terminal addition of plant-specific mannose for improved uptake
(Sabalza et al., 2014; Shaaltiel et al., 2007). The challenges associated with glycosylation of
plant-produced antibodies are considered one of the major regulatory bottlenecks of the
“plantibody” paradigm (Obembe et al., 2011). In our study, the impact of temporary
immersion shoot regeneration on glycosylation of Guy’s 13 antibody was not characterised.
As a future work, the glycosylation pattern and glycan quantitative ratio can be determined
by exoglycosidases digestion followed by HPLC analysis or GC-MS (Shaaltiel et al., 2007).
7.5 Implementation of robust bioprocesses for biopharmaceutical
synthesis
The studies outlined in this dissertation have investigated the feasibility of temporary
immersion shoot regeneration from callus as the basis for a bioprocess platform for high-
yield synthesis of biotherapeutics. Temporary immersion culture of N. tabacum biomass in
small-scale pneumatic systems (RITA® bioreactors) and a large-scale mechanical system
was undertaken. Such systems can be implemented with little capital equipment,
instrumentation or expertise, as opposed to conventional ‘stainless steel’ microbial
fermentation facilities. Standard temperature-controlled micropropagation or greenhouse
facilities can be used, such as those used in commercial horticulture, though laminar flow
hoods and extensive light and space would be required. Power requirements would be
considerably less than standard fermentation facilities. A simple inexpensive low-power air
pump can provide pneumatic suspension of liquid media for approximately 25 RITA®.
Although lighting would be a major energy sink, low power light-emitting diodes (LED)
could be used; these have been shown to effectively stimulate growth in a number of
micropropagative processes (Nhut et al., 2003; Okamoto et al., 1996; Tan Nhut et al., 2001).
Low-tech micropropagative facilities can be set up easily in developing countries, for
example, to provide cheap vaccines for the populace.
168
Much of the focus of molecular farming research has been optimisation of recombinant
protein yields, through molecular or growth strategies (Twyman et al., 2013). Unfortunately,
relatively little development of downstream processes for product extraction and purification
has been undertaken (Fischer et al., 2012). Downstream processing routes must conform to
GMP standards and result in a sufficiently pure and homogeneous pharmaceutical product,
according to regulatory requirements. Robust downstream processing technologies are well-
established for endotoxin removal from bacteria and viruses from mammalian cells (Fischer
et al., 2012). Since plants do not contain endotoxins or mammalian viruses, it is expected that
downstream processes for plant-based systems can be simplified from established
technologies. Downstream processing can account for 80% of the cost of plant-based
bioprocesses, so there are significant savings to be gained from optimisation (Evangelista et
al., 1998; Kusnadi et al., 1997).
169
Bibliography
Aarts, M.G.M., and M.W.E.J. Fiers. 2003. What drives plant stress genes? Trends Plant Sci. 8:99-102. Abbasin, Z., S. Zamani, S. Movahedi, G. Khaksar, and B.E.S. Tabatabaei. 2010. In vitro
micropropagation of yew (Taxus baccata) and production of plantlets. Biotechnology. 9:48-54.
Adam, Z., A. Rudella, and K.J. van Wijk. 2006. Recent advances in the study of Clp, FtsH and other proteases located in chloroplasts. Current Opinion in Plant Biology. 9:234-240.
Adelberg, J. 2006. Agitated, Thin-Films Of Liquid Media For Efficient Micropropagation. In Plan Tissue Culture Engineering. Vol. 6. S.D. Gupta and Y. Ibaraki, editors. Springer Netherlands. 101-117.
Ahmad, N. 2012. Developing new tools for the expression of foreign proteins in tobacco chloroplasts. Imperial College London.
Ahmad, N., F. Michoux, J. McCarthy, and P. Nixon. 2012a. Expression of the affinity tags, glutathione-S-transferase and maltose-binding protein, in tobacco chloroplasts. Planta. 235:863-871.
Ahmad, N., F. Michoux, and P.J. Nixon. 2012b. Investigating the Production of Foreign Membrane Proteins in Tobacco Chloroplasts: Expression of an Algal Plastid Terminal Oxidase. PLOS ONE. 7:e41722.
Ahmad, N., and Z. Mukhtar. 2013. Green factories: plastids for the production of foreign proteins at high levels. Gene Therapy and Molecular Biology. 15:14-29.
Ainsworth, E.A., and D.R. Bush. 2011. Carbohydrate Export from the Leaf: A Highly Regulated Process and Target to Enhance Photosynthesis and Productivity. Plant Physiol. 155:64-69.
Aitken-Christie, J. 1991. Automation. 363-388 pp. Aitken-Christie, J., and C. Jones. 1987. Towards automation - radiata pine shoot hedges in vitro. Plant
Cell Tissue Organ Cult. 8:185-196. Ajjawi, I., and D. Shintani. 2004. Engineered plants with elevated vitamin E: a nutraceutical success
story. Trends Biotechnol. 22:104-107. Akin-Idowu, P.E., D.O. Ibitoye, and O.T. Ademoyegun. 2009. Tissue culture as a plant production
technique for horticultural crops. Afr. J. Biotechnol. 8:3782-3788. Akita, M., T. Shigeoka, Y. Koizumi, and M. Kawamura. 1994. Mass propagation of shoots of Stevia
rebaudiana using a large scale bioreactor. Plant Cell Reports. 13:180-183. Albarran, J., B. Bertrand, M. Lartaud, and H. Etienne. 2005. Cycle characteristics in a temporary
immersion bioreactor affect regeneration, morphology, water and mineral status of coffee (Coffea arabica) somatic embryos. Plant Cell Tissue Organ Cult. 81:27-36.
Aldridge, G.M., D.M. Podrebarac, W.T. Greenough, and I.J. Weiler. 2008. The use of total protein stains as loading controls: An alternative to high-abundance single-protein controls in semi-quantitative immunoblotting. Journal of Neuroscience Methods. 172:250-254.
Alvard, D., F. Cote, and C. Teisson. 1993. Comparison of methods of liquid-medium culture for banana micropropagation - effects of temporary immersion of explants. Plant Cell Tissue Organ Cult. 32:55-60.
Alvim, F.C., S.M.B. Carolino, J.C.M. Cascardo, C.C. Nunes, C.A. Martinez, W.C. Otoni, and E.P.B. Fontes. 2001. Enhanced Accumulation of BiP in Transgenic Plants Confers Tolerance to Water Stress. Plant Physiol. 126:1042-1054.
Anderson, R., X.M. Gao, A. Papakonstantinopoulou, M. Roberts, and G. Dougan. 1996. Immune response in mice following immunization with DNA encoding fragment C of tetanus toxin. Infection and Immunity. 64:3168-3173.
170
Anon. 2012. Taliglucerase (Elelyso) for Gaucher Disease. Medical Letter on Drugs and Therapeutics. 54:56-56.
Apel, W., and R. Bock. 2009. Enhancement of Carotenoid Biosynthesis in Transplastomic Tomatoes by Induced Lycopene-to-Provitamin A Conversion. Plant Physiol. 151:59-66.
Arencibia, A.D., A. Bernal, L. Yang, L. Cortegaza, E.R. Carmona, A. Pérez, C.-J. Hu, Y.-R. Li, C.M. Zayas, and I. Santana. 2008. New role of phenylpropanoid compounds during sugarcane micropropagation in Temporary Immersion Bioreactors (TIBs). Plant Science. 175:487-496.
Arigita, L., A. González, and R.S. Tamés. 2002. Influence of CO2 and sucrose on photosynthesis and transpiration of Actinidia deliciosa explants cultured in vitro. Physiologia Plantarum. 115:166-173.
Artsaenko, O., B. Kettig, U. Fiedler, U. Conrad, and K. Düring. 1998. Potato tubers as a biofactory for recombinant antibodies. Molecular Breeding. 4:313-319.
Atkin, O.K., and W.R. Cummins. 1994. The Effect of Nitrogen Source on Growth, Nitrogen Economy and Respiration of Two High Arctic Plant Species Differing in Relative Growth Rate. Functional Ecology. 8:389-399.
Avni, A., and M. Edelman. 1991. Direct selection for paternal inheritance of chloroplasts in sexual progeny of Nicotiana. Mol. Gen. Genet. 225:273-277.
Babaoglu, M., and M. Yorgancilar. 2000. TDZ-specific plant regeneration in salad burnet. Plant Cell, Tissue and Organ Culture. 63:31-34.
Bai, Y., and C.E. Glatz. 2003. Capture of a recombinant protein from unclarified canola extract using streamline expanded bed anion exchange. Biotechnol. Bioeng. 81:855-864.
Balen, B., M. Tkalec, D. Pavoković, B. Pevalek-Kozlina, and M. Krsnik-Rasol. 2009. Growth Conditions in In Vitro Culture Can Induce Oxidative Stress in Mammillaria gracilis Tissues. J Plant Growth Regul. 28:36-45.
Baque, M.A., S.H. Moh, E.J. Lee, J.J. Zhong, and K.Y. Paek. 2012. Production of biomass and useful compounds from adventitious roots of high-value added medicinal plants using bioreactor. Biotechnol Adv. 30:1255-1267.
Bar-Yosef, B., N.S. Mattson, and H.J. Lieth. 2009. Effects of NH4 : NO3 : urea ratio on cut roses yield, leaf nutrients content and proton efflux by roots in closed hydroponic system. Scientia Horticulturae. 122:610-619.
Bardor, M., C. Faveeuw, A.C. Fitchette, D. Gilbert, L. Galas, F. Trottein, L. Faye, and P. Lerouge. 2003. Immunoreactivity in mammals of two typical plant glyco-epitopes, core alpha(1,3)-fucose and core xylose. Glycobiology. 13:427-434.
Barkan, A. 1988. Proteins encoded by a complex chloroplast transcription unit are each translated from both monocistronic and polycistronic mRNAs. The EMBO journal. 7:2637.
Barkan, A. 2011. Expression of plastid genes: organelle-specific elaborations on a prokaryotic scaffold. Plant Physiol. 155:1520-1532.
Bartelheimer, M., and P. Poschlod. 2014. The response of grassland species to nitrate versus ammonium coincides with their pH optima. Journal of Vegetation Science. 25:760-770.
Batra, S.K., M. Jain, U.A. Wittel, S.C. Chauhan, and D. Colcher. 2002. Pharmacokinetics and biodistribution of genetically engineered antibodies. Current Opinion in Biotechnology. 13:603-608.
Baumal, R., M. Potter, and M.D. Scharff. 1971. Synthesis, assembly, and secretion of gamma globulin by mouse myeloma cells. 3. Assembly of the three subclasses of IgG. The Journal of Experimental Medicine. 134:1316-1334.
Benchabane, M., C. Goulet, D. Rivard, L. Faye, V. Gomord, and D. Michaud. 2008. Preventing unintended proteolysis in plant protein biofactories. Plant Biotechnol. J. 6:633-648.
Bernstein, H.H., E.P. Rothstein, P.P. Associates, M.E. Pichichero, J.L. Green, E. Pediatrics, K.S. Reisinger, M.M. Blatter, J. Halpern, A.M. Arbeter, D.I. Bernstein, V. Smith, S.S. Long, H. Rathfon, and D.S. Krause. 1995. Reactogenicity and immunogenicity of a three-component
171
acellular pertussis vaccine administered as the primary series to 2, 4 and 6 month old infants in the United States. Vaccine. 13:1631-1635.
Berry, J.D. 2005. Rational monoclonal antibody development to emerging pathogens, biothreat agents and agents of foreign animal disease: The antigen scale. The Veterinary Journal. 170:193-211.
Berry, J.D., and R.G. Gaudet. 2011. Antibodies in infectious diseases: polyclonals, monoclonals and niche biotechnology. New Biotechnology. 28:489-501.
Bewley, J.D. 1997. Seed germination and dormancy. The plant cell. 9:1055. Bhatia, P., and N. Ashwath. 2005. Effect of medium pH on shoot regeneration from the cotyledonary
explants of tomato. Biotechnology. 4:7-10. Birch-Machin, I., C.A. Newell, J.M. Hibberd, and J.C. Gray. 2004. Accumulation of rotavirus VP6
protein in chloroplasts of transplastomic tobacco is limited by protein stability. Plant Biotechnol. J. 2:261-270.
Birch, J.R., and A.J. Racher. 2006. Antibody production. Advanced Drug Delivery Reviews. 58:671-685. Bird, R.E., and B.W. Walker. 1991. Single chain antibody variable regions. Trends Biotechnol. 9:132-
137. Bock, R. 2007. Plastid biotechnology: prospects for herbicide and insect resistance, metabolic
engineering and molecular farming. Current Opinion in Biotechnology. 18:100-106. Bock, R. 2014. Genetic engineering of the chloroplast: novel tools and new applications. Current
Opinion in Biotechnology. 26:7-13. Bock, R., and M.S. Khan. 2004. Taming plastids for a green future. Trends Biotechnol. 22:311-318. Bogorad, L. 2000. Engineering chloroplasts: an alternative site for foreign genes, proteins, reactions
and products. Trends Biotechnol. 18:257-263. Boivin, E.B., E. Lepage, D.P. Matton, G. De Crescenzo, and M. Jolicoeur. 2010. Transient expression of
antibodies in suspension plant cell suspension cultures is enhanced when co-transformed with the tomato bushy stunt virus p19 viral suppressor of gene silencing. Biotechnol Prog. 26:1534-1543.
Boothe, J., C. Nykiforuk, Y. Shen, S. Zaplachinski, S. Szarka, P. Kuhlman, E. Murray, D. Morck, and M.M. Moloney. 2010. Seed-based expression systems for plant molecular farming. Plant Biotechnol. J. 8:588-606.
Bourgaud, F., A. Gravot, S. Milesi, and E. Gontier. 2001. Production of plant secondary metabolites: a historical perspective. Plant Science. 161:839-851.
Boyhan, D., and H. Daniell. 2011. Low-cost production of proinsulin in tobacco and lettuce chloroplasts for injectable or oral delivery of functional insulin and C-peptide. Plant Biotechnol. J. 9:585-598.
Boynton, J.E., N.W. Gillham, E.H. Harris, J.P. Hosler, A.M. Johnson, A.R. Jones, B.L. Randolphanderson, D. Robertson, T.M. Klein, K.B. Shark, and J.C. Sanford. 1988. Chloroplast transformation in chlamydomonas with high-velocity microprojectiles. Science. 240:1534-1538.
Bradford, M.M. 1976. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Analytical Biochemistry. 72:248-254.
Brodzik, R., M. Glogowska, K. Bandurska, M. Okulicz, D. Deka, K. Ko, J. van der Linden, J.H.W. Leusen, N. Pogrebnyak, M. Golovkin, Z. Steplewski, and H. Koprowski. 2006. Plant-derived anti-Lewis Y mAb exhibits biological activities for efficient immunotherapy against human cancer cells. Proceedings of the National Academy of Sciences. 103:8804-8809.
Brodzik, R., S. Spitsin, N. Pogrebnyak, K. Bandurska, C. Portocarrero, K. Andryszak, H. Koprowski, and M. Golovkin. 2009. Generation of plant-derived recombinant DTP subunit vaccine. Vaccine. 27:3730-3734.
Brorson, K., and A.Y. Jia. 2014. Therapeutic monoclonal antibodies and consistent ends: terminal heterogeneity, detection, and impact on quality. Current Opinion in Biotechnology. 30:140-146.
172
Budzianowski, J. 2010. Tobacco -a highly efficient producer of vaccines. Przeglad lekarski. 67:1071-1076.
Busse, U., V. Levee, S. Trepanier, and L. Vezina. 2002. Production of Antibodies in Alfalfa (Medicago Sativa). In Molecular Farming of Plants and Animals for Human and Veterinary Medicine. L. Erickson, W.J. Yu, J. Brandle, and R. Rymerson, editors. Springer Netherlands. 237-257.
Butenko, R.G., A.K. Lipsky, N.D. Chernyak, and H.C. Arya. 1984. Changes in culture medium pH by cell suspension cultures of Dioscorea deltoidea. Plant Science Letters. 35:207-212.
Calvo, A.C., S. Oliván, R. Manzano, P. Zaragoza, J. Aguilera, and R. Osta. 2012. Fragment C of Tetanus Toxin: New Insights into Its Neuronal Signaling Pathway. International Journal of Molecular Sciences. 13:6883-6901.
Campbell, P.N. 1992. Biochemistry and molecular biology. Biochemical Education. 20:158-165. Casadevall, A. 1998. Antibody-based therapies as anti-infective agents. Expert opinion on
investigational drugs. 7:307-321. Casadevall, A., and M.D. Scharff. 1995. Return to the Past: The Case for Antibody-Based Therapies in
Infectious Diseases. Clinical Infectious Diseases. 21:150-161. Castro-Concha, L., R. Escobedo, and M. Miranda-Ham. 2006. Measurement of Cell Viability in In Vitro
Cultures. In Plant Cell Culture Protocols. Vol. 318. V. Loyola-Vargas and F. Vázquez-Flota, editors. Humana Press. 71-76.
Chaleff, R.S. 1982. Induction, maintenance, and differentiation of rice callus cultures on ammonium as sole nitrogen source. Plant Cell, Tissue and Organ Culture. 2:29-37.
Chamberlain, D., and C.N. Stewart. 1999. Transgene escape and transplastomics. Nat Biotech. 17:330-331.
Chargelegue, D., P.M.W. Drake, P. Obregon, A. Prada, N. Fairweather, and J.K.-C. Ma. 2005. Highly Immunogenic and Protective Recombinant Vaccine Candidate Expressed in Transgenic Plants. Infection and Immunity. 73:5915-5922.
Chaves, M.M., J.S. Pereira, J. Maroco, M.L. Rodrigues, C.P.P. Ricardo, M.L. Osório, I. Carvalho, T. Faria, and C. Pinheiro. 2002. How Plants Cope with Water Stress in the Field? Photosynthesis and Growth. Annals of Botany. 89:907-916.
Cheingsong-Popov, R., C. Panagiotidi, S. Bowcock, A. Aronstam, J. Wadsworth, and J. Weber. 1991. Relation between humoral responses to HIV gag and env proteins at seroconversion and clinical outcome of HIV infection. 23-26 pp.
Chen, Q. 2008. Expression and purification of pharmaceutical proteins in plants. Biol Eng. 1:291-321. Cheng, L., H.P. Li, B. Qu, T. Huang, J.X. Tu, T.D. Fu, and Y.C. Liao. 2010. Chloroplast transformation of
rapeseed (Brassica napus) by particle bombardment of cotyledons. Plant Cell Rep. 29:371-381.
Chisti, Y., and M. Moo-Young. 1989. On the calculation of shear rate and apparent viscosity in airlift and bubble column bioreactors. Biotechnol. Bioeng. 34:1391-1392.
Choffe, K., J. Victor, S. Murch, and P. Saxena. 2000. In vitro regeneration of Echinacea purpurea L.: Direct somatic embryogenesis and indirect shoot organogenesis in petiole culture. In Vitro Cellular & Developmental Biology - Plant. 36:30-36.
Choi, A.H.C., M. Basu, M.M. McNeal, J. Flint, J.L. VanCott, J.D. Clements, and R.L. Ward. 2000. Functional Mapping of Protective Domains and Epitopes in the Rotavirus VP6 Protein. Journal of Virology. 74:11574-11580.
Choi, Y.-E., Y.-S. Kim, and K.-Y. Paek. 2006. Types and designs of bioreactors for hairy root culture. In Plan Tissue Culture Engineering. Springer. 161-172.
Ciarmiello, L.F., P. Woodrow, A. Fuggi, G. Pontecorvo, and P. Carillo. 2011. Plant Genes for Abiotic Stress.
Clarke, J.L., and H. Daniell. 2011. Plastid biotechnology for crop production: present status and future perspectives. Plant Mol Biol. 76:211-220.
Clemensson-Lindell, A., and H. Persson. 1995. Fine-root vitality in a Norway spruce stand subjected to various nutrient supplies. Plant Soil. 168-169:167-172.
173
Cohen, S.N., A.C.Y. Chang, H.W. Boyer, and R.B. Helling. 1973. Construction of Biologically Functional Bacterial Plasmids In Vitro. Proceedings of the National Academy of Sciences. 70:3240-3244.
Colgan, R., C. Atkinson, M. Paul, S. Hassan, P.W. Drake, A. Sexton, S. Santa-Cruz, D. James, K. Hamp, C. Gutteridge, and J.-C. Ma. 2010. Optimisation of contained Nicotiana tabacum cultivation for the production of recombinant protein pharmaceuticals. Transgenic Res. 19:241-256.
Colwell, R.R. 2002. Fulfilling the promise of biotechnology. Biotechnol. Adv. 20:215-228. Commandeur, U., R.M. Twyman, and R. Fischer. 2003. The biosafety of molecular farming in plants.
AgBiotechNet. 5:1-9. Compton, M., and J. Koch. 2001. Influence of plant preservative mixture (PPM)TM on adventitious
organogenesis in melon, petunia, and tobacco. In Vitro Cellular & Developmental Biology - Plant. 37:259-261.
Coulson, J.M., J.F. Richardson, J.R. Backhurst, and J.H. Harker. 1999. Coulson and Richardson's Chemical Engineering Volume 1 - Fluid Flow, Heat Transfer and Mass Transfer (6th Edition). Elsevier. 108.
Cousson, A., and K.T.T. Van. 1993. Influence of ionic composition of the culture medium on de novo flower formation in tobacco thin cell layers. Canadian Journal of Botany. 71:506-511.
Craufurd, P., and T. Wheeler. 2009. Climate change and the flowering time of annual crops. Journal of Experimental Botany. 60:2529-2539.
Crouch, S.P.M., R. Kozlowski, K.J. Slater, and J. Fletcher. 1993. The use of ATP bioluminescence as a measure of cell proliferation and cytotoxicity. Journal of Immunological Methods. 160:81-88.
D'Aoust, M.-A., U. Busse, M. Martel, P. Lerouge, D. Levesque, and L.-P. Vézina. 2004. Perennial Plants as a Production System for Pharmaceuticals. In Handbook of Plant Biotechnology. John Wiley & Sons, Ltd.
da Silva, A.B., M. Pasqual, J.B. Teixeira, and A.G. De Araujo. 2007. Micropropagation methods of pineapple. Pesqui. Agropecu. Bras. 42:1257-1260.
Daniell, H., S. Chebolu, S. Kumar, M. Singleton, and R. Falconer. 2005. Chloroplast-derived vaccine antigens and other therapeutic proteins. Vaccine. 23:1779-1783.
Daniell, H., R. Datta, S. Varma, S. Gray, and S.B. Lee. 1998. Containment of herbicide resistance through genetic engineering of the chloroplast genome. Nat. Biotechnol. 16:345-348.
Daniell, H., M.S. Khan, and L. Allison. 2002. Milestones in chloroplast genetic engineering: an environmentally friendly era in biotechnology. Trends Plant Sci. 7:84-91.
Daniell, H., S.B. Lee, T. Panchal, and P.O. Wiebe. 2001a. Expression of the native cholera toxin B subunit gene and assembly as functional oligomers in transgenic tobacco chloroplasts. Journal of Molecular Biology. 311:1001-1009.
Daniell, H., G. Ruiz, B. Denes, L. Sandberg, and W. Langridge. 2009. Optimization of codon composition and regulatory elements for expression of human insulin like growth factor-1 in transgenic chloroplasts and evaluation of structural identity and function. BMC Biotechnol. 9:33.
Daniell, H., S.J. Streatfield, and K. Wycoff. 2001b. Medical molecular farming: production of antibodies, biopharmaceuticals and edible vaccines in plants. Trends Plant Sci. 6:219-226.
Davies, H.M. 2010. Commercialization of whole-plant systems for biomanufacturing of protein products: evolution and prospects. Plant Biotechnol. J. 8:845-861.
de Bruijn, H. 1942. The viscosity of suspensions of spherical particles. (The fundamental η-c and φ relations). Recueil des Travaux Chimiques des Pays-Bas. 61:863-874.
De Cosa, B., W. Moar, S.B. Lee, M. Miller, and H. Daniell. 2001. Overexpression of the Bt cry2Aa2 operon in chloroplasts leads to formation of insecticidal crystals. Nat. Biotechnol. 19:71-74.
de la Viña, G., F. Pliego-Alfaro, S.P. Driscoll, V.J. Mitchell, M.A. Parry, and D.W. Lawlor. 1999. Effects of CO2 and sugars on photosynthesis and composition of avocado leaves grown in vitro. Plant Physiology and Biochemistry. 37:587-595.
De Neve, M., H. Van Houdt, A.-M. Bruyns, M. Van Montagu, and A. Depicker. 1998. Screening for Transgenic Lines with Stable and Suitable Accumulation Levels of a Heterologous Protein. In
174
Recombinant Proteins from Plants. Vol. 3. C. Cunningham and A.R. Porter, editors. Humana Press. 203-227.
De Wolf, F., J. Goudsmit, D.A. Paul, J. Lange, C. Hooijkaas, P. Schellekens, R.A. Coutinho, and J. van der Noordaa. 1987. Risk of AIDS related complex and AIDS in homosexual men with persistent HIV antigenaemia. British medical journal (Clinical research ed.). 295:569.
Debergh, P.C. 1983. Effects of agar brand and concentration on the tissue-culture medium. Physiologia Plantarum. 59:270-276.
Decker, E.L., and R. Reski. 2004. The moss bioreactor. Current Opinion in Plant Biology. 7:166-170. Decker, E.L., and R. Reski. 2007. Moss bioreactors producing improved biopharmaceuticals. Current
Opinion in Biotechnology. 18:393-398. DeGray, G., K. Rajasekaran, F. Smith, J. Sanford, and H. Daniell. 2001. Expression of an antimicrobial
peptide via the chloroplast genome to control phytopathogenic bacteria and fungi. Plant Physiol. 127:852-862.
Dekker, J.P., and E.J. Boekema. 2005. Supramolecular organization of thylakoid membrane proteins in green plants. Biochimica et Biophysica Acta (BBA) - Bioenergetics. 1706:12-39.
Demeyer, R. 2011. Evaluation of Arabidopsis spp. as a production platform for molecular farming. Ghent University.
Dennehy, P.H. 2008. Rotavirus Vaccines: an Overview. Clinical Microbiology Reviews. 21:198-208. Dewir, Y.H., D. Chakrabarty, M.B. Ali, E.J. Hahn, and K.Y. Paek. 2006. Lipid peroxidation and
antioxidant enzyme activities of Euphorbia millii hyperhydric shoots. Environmental and Experimental Botany. 58:93-99.
Dietmair, S., L.K. Nielsen, and N.E. Timmins. 2012. Mammalian cells as biopharmaceutical production hosts in the age of omics. Biotechnology Journal. 7:75-89.
Dinarvand, M., M. Rezaee, M. Masomian, S.D. Jazayeri, M. Zareian, S. Abbasi, and A.B. Ariff. 2013. Effect of C/N Ratio and Media Optimization through Response Surface Methodology on Simultaneous Productions of Intra- and Extracellular Inulinase and Invertase from Aspergillus niger ATCC 20611. BioMed Research International. 2013:13.
Dinnis, D.M., and D.C. James. 2005. Engineering mammalian cell factories for improved recombinant monoclonal antibody production: lessons from nature? Biotechnol. Bioeng. 91:180-189.
Doan, L.X., M. Li, C. Chen, and Q. Yao. 2005. Virus-like particles as HIV-1 vaccines. Reviews in Medical Virology. 15:75-88.
Dodds, J.H. 1988. Tissue culture technology: Practical application of sophisticated methods. American Potato Journal. 65:167-180.
Dong, J.-L., B. Zhou, G. Sheng, and T. Wang. 2005. Transgenic Tobacco Expressing a Modified VP6 Gene Protects Mice Against Rotavirus Infection. Journal of Integrative Plant Biology. 47:978-987.
Doran, P.M. 2000. Foreign protein production in plant tissue cultures. Current Opinion in Biotechnology. 11:199-204.
Doran, P.M. 2006. Foreign protein degradation and instability in plants and plant tissue cultures. Trends Biotechnol. 24:426-432.
Doran, P.M. 2013. Therapeutically important proteins from in vitro plant tissue culture systems. Current medicinal chemistry. 20:1047-1055.
Dörmann, P. 2001. Galactolipids in Plant Membranes. In eLS. John Wiley & Sons, Ltd. Drake, P.M., D.M. Chargelegue, N.D. Vine, C.J. van Dolleweerd, P. Obregon, and J.K. Ma. 2003.
Rhizosecretion of a monoclonal antibody protein complex from transgenic tobacco roots. Plant Mol Biol. 52:233-241.
Drake, P.M.W., T. Barbi, A. Sexton, E. McGowan, J. Stadlmann, C. Navarre, M.J. Paul, and J.K.-C. Ma. 2009. Development of rhizosecretion as a production system for recombinant proteins from hydroponic cultivated tobacco. The FASEB Journal. 23:3581-3589.
Dubranszki, J., and J.A.T. da Silva. 2010. Micropropagation of apple - A review. Biotechnol. Adv. 28:462-488.
175
Dufourmantel, N., M. Dubald, M. Matringe, H. Canard, F. Garcon, C. Job, E. Kay, J.-P. Wisniewski, J.-M. Ferullo, B. Pelissier, A. Sailland, and G. Tissot. 2007. Generation and characterization of soybean and marker-free tobacco plastid transformants over-expressing a bacterial 4-hydroxyphenylpyruvate dioxygenase which provides strong herbicide tolerance. Plant Biotechnol. J. 5:118-133.
Dunlop, E.H., P.K. Namdev, and M.Z. Rosenberg. 1994. Effect of fluid shear forces on plant cell suspensions. Chemical Engineering Science. 49:2263-2276.
During, K. 1988. Wound-inducible expression and secretion of T4 lysozyme and monoclonal antibodies in Nicotiana tabacum. Inaugral Dissertation to Obtain a Doctorate at the Mathematisch-Naturwissenchaftlichen Fakultät der Universität zu Köln. Köln ed:1-90.
Dyer, W.B., H. Kuipers, M.W. Coolen, A.F. Geczy, J. Forrester, C. Workman, and J.S. Sullivan. 2002. Correlates of antiviral immune restoration in acute and chronic HIV type 1 infection: sustained viral suppression and normalization of T cell subsets. AIDS research and human retroviruses. 18:999-1010.
Eibl, C., Z.R. Zou, A. Beck, M. Kim, J. Mullet, and H.U. Koop. 1999. In vivo analysis of plastid psbA, rbcL and rpl32 UTR elements by chloroplast transformation: tobacco plastid gene expression is controlled by modulation of transcript levels and translation efficiency. Plant J. 19:333-345.
Eibl, R., and D. Eibl. 2008. Design of bioreactors suitable for plant cell and tissue cultures. Phytochemistry Reviews. 7:593-598.
Eibl, R., S. Kaiser, R. Lombriser, and D. Eibl. 2010. Disposable bioreactors: the current state-of-the-art and recommended applications in biotechnology. Applied Microbiology and Biotechnology. 86:41-49.
Eisenberg, D., H.S. Gill, G.M.U. Pfluegl, and S.H. Rotstein. 2000. Structure–function relationships of glutamine synthetases. Biochimica et Biophysica Acta (BBA) - Protein Structure and Molecular Enzymology. 1477:122-145.
Engelen, F., A. Schouten, J. Molthoff, J. Roosien, J. Salinas, W. Dirkse, A. Schots, J. Bakker, F. Gommers, M. Jongsma, D. Bosch, and W. Stiekema. 1994. Coordinate expression of antibody subunit genes yields high levels of functional antibodies in roots of transgenic tobacco. Plant Mol.Biol. 26:1701-1710.
Erickson, J. 1998. Assembly of Photosystem II. In The Molecular Biology of Chloroplasts and Mitochondria in Chlamydomonas. Vol. 7. J.D. Rochaix, M. Goldschmidt-Clermont, and S. Merchant, editors. Springer Netherlands. 255-285.
Escalant, J.V., C. Teisson, and F. Cote. 1994. Amplified somatic embryogenesis from male flowers of triploid banana and plantain cultivars (Musa spp.). In Vitro Cell. Dev. Biol.-Plant. 30P:181-186.
Escalona, M., J.C. Lorenzo, B. Gonzalez, M. Daquinta, J.L. Gonzalez, Y. Desjardins, and C.G. Borroto. 1999. Pineapple (Ananas comosus L-Merr) micropropagation in temporary immersion systems. Plant Cell Reports. 18:743-748.
Esposito, D., and D.K. Chatterjee. 2006. Enhancement of soluble protein expression through the use of fusion tags. Current Opinion in Biotechnology. 17:353-358.
Etienne, H., and M. Berthouly. 2002. Temporary immersion systems in plant micropropagation. Plant Cell Tissue Organ Cult. 69:215-231.
Etienne, H., M. Lartaud, N. MichauxFerriere, M.P. Carron, M. Berthouly, and C. Teisson. 1997. Improvement of somatic embryogenesis in Hevea brasiliensis (Mull Arg) using the temporary immersion technique. In Vitro Cell. Dev. Biol.-Plant. 33:81-87.
Evangelista, R.L., A.R. Kusnadi, J.A. Howard, and Z.L. Nikolov. 1998. Process and Economic Evaluation of the Extraction and Purification of Recombinant β-Glucuronidase from Transgenic Corn. Biotechnology Progress. 14:607-614.
Evans, N.E. 1993. A Preliminary Study on the Effects of Nitrogen Supply on the Growth In Vitro of Nine Potato Genotypes (Solanum spp). Journal of Experimental Botany. 44:837-841.
176
Faye, L., and V. Gomord. 2010. Success stories in molecular farming—a brief overview. Plant Biotechnol. J. 8:525-528.
Faye, M., A. David, and A. Lamant. 1986. Nitrate reductase activity and nitrate accumulation in in vitro produced axillary shoots, plantlets and seedlings of Pinus pinaster. Plant Cell Rep. 5:368-371.
Featherstone, J.D.B. 2000. The science and practice of caries prevention. The Journal of the American Dental Association. 131:887-899.
Findlay, J.W.A., and R.F. Dillard. 2007. Appropriate calibration curve fitting in ligand binding assays. AAPS J. 9:E260-E267.
Firoozabady, E., and N. Gutterson. 2003. Cost-effective in vitro propagation methods for pineapple. Plant Cell Reports. 21:844-850.
Fischer, R., S. Schillberg, J.F. Buyel, and R.M. Twyman. 2013. Commercial aspects of pharmaceutical protein production in plants. Curr Pharm Des. 19:5471-5477.
Fischer, R., S. Schillberg, S. Hellwig, R.M. Twyman, and J. Drossard. 2012. GMP issues for recombinant plant-derived pharmaceutical proteins. Biotechnol. Adv. 30:434-439.
Fontes, M.A., W.C. Otoni, S.M.B. Carolino, S.H. Brommonschenkel, E.P.B. Fontes, M. Fári, and R.P. Louro. 1999. Hyperhydricity in pepper plants regenerated in vitro: involvement of BiP (Binding Protein) and ultrastructural aspects. Plant Cell Reports. 19:81-87.
Fournier, D., C. Bonnelle, and Y. Tourte. 1991. Ultrastructural features of soybean somatic cells at the beginning of an organogenic process: toward a new concept. Biology of the Cell. 73:99-105.
Fink, J.S. Fry, G.R. Galluppi, S.B. Goldberg, N.L. Hoffmann, and S.C. Woo. 1983. Expression of bacterial genes in plant cells. Proceedings of the National Academy of Sciences. 80:4803-4807.
Franklin, K.A., V.S. Larner, and G.C. Whitelam. 2005. The signal transducing photoreceptors of plants. The International journal of developmental biology. 49:653-664.
Frey, S., and D. Gorlich. 2014. Purification of protein complexes of defined subunit stoichiometry using a set of orthogonal, tag-cleaving proteases. Journal of chromatography. A. 1337:106-115.
Fujita, Y. 1988. Shikonin: Production by Plant (Lithospermum erythrorhizon) Cell Cultures. In Medicinal and Aromatic Plants I. Vol. 4. Y.P.S. Bajaj, editor. Springer Berlin Heidelberg. 225-236.
Fukao, T., and J. Bailey-Serres. 2004. Plant responses to hypoxia – is survival a balancing act? Trends Plant Sci. 9:449-456.
Galzy, R., and D. Compan. 1992. Remarks on mixotrophic and autotrophic carbon nutrition of Vitis plantlets cultured in vitro. Plant Cell, Tissue and Organ Culture. 31:239-244.
Gamborg, O.L. 1970. The Effects of Amino Acids and Ammonium on the Growth of Plant Cells in Suspension Culture. Plant Physiol. 45:372-375.
Gardi, T., E. Piccioni, and A. Standardi. 1999. Effect of bead nutrient composition on regrowth of stored in vitro-derived encapsulated microcuttings of different woody species. Journal of Microencapsulation. 16:13-25.
Gaspar, T., T. Franck, B. Bisbis, C. Kevers, L. Jouve, J.F. Hausman, and J. Dommes. 2002. Concepts in plant stress physiology. Application to plant tissue cultures. Plant Growth Regul. 37:263-285.
Gavrilescu, M., and Y. Chisti. 2005. Biotechnology—a sustainable alternative for chemical industry. Biotechnol. Adv. 23:471-499.
George, E.F., A. Hall, and G.J. de Klerk. 2007. Plant Propagation by Tissue Culture: Volume 1. The Background. Springer.
177
George, M.W., and R.R. Tripepi. 2001. Plant Preservative Mixture™ can affect shoot regeneration from leaf explants of Chrysanthemum, European birch, and Rhododendron. Hortscience. 36:768-769.
Georgiev, M.I., J. Weber, and A. Maciuk. 2009. Bioprocessing of plant cell cultures for mass production of targeted compounds. Applied Microbiology and Biotechnology. 83:809-823.
Georgiev, V., M. Ilieva, T. Bley, and A. Pavlov. 2008. Betalain production in plant in vitro systems. Acta Physiol. Plant. 30:581-593.
Georgiev, V., A. Schumann, A. Pavlov, and T. Bley. 2014. Temporary immersion systems in plant biotechnology. Engineering in Life Sciences:n/a-n/a.
Gill, R., and P.K. Saxena. 1993. Somatic embryogenesis in Nicotiana tabacum - induction by thidiazuron of direct embryo differentiation from cultured leaf-disks. Plant Cell Reports. 12:154-159.
Gils, M., R. Kandzia, S. Marillonnet, V. Klimyuk, and Y. Gleba. 2005. High-yield production of authentic human growth hormone using a plant virus-based expression system. Plant Biotechnol. J. 3:613-620.
Gisby, M.F., E.A. Mudd, and A. Day. 2012. Growth of transplastomic cells expressing D-amino acid oxidase in chloroplasts is tolerant to D-alanine and inhibited by D-valine. Plant Physiol. 160:2219-2226.
Glacken, M.W., R.J. Fleischaker, and A.J. Sinskey. Mammalian cell culture: engineering principles and scale-up. Trends Biotechnol. 1:102-108.
Gleba, Y., S. Marillonnet, and V. Klimyuk. 2004. Design of safe and biologically contained transgenic plants: tools and technologies for controlled transgene flow and expression. Biotechnology & genetic engineering reviews. 21:325-367.
Gloe, T., H.Y. Sohn, G.A. Meininger, and U. Pohl. 2002. Shear Stress-induced Release of Basic Fibroblast Growth Factor from Endothelial Cells Is Mediated by Matrix Interaction via Integrin αVβ3. Journal of Biological Chemistry. 277:23453-23458.
Golds, T., P. Maliga, and H.U. Koop. 1993. Stable plastid transformation in peg-treated protoplasts of Nicotiana tabacum. Bio-Technology. 11:95-97.
Gomord, V., A.-C. Fitchette, L. Menu-Bouaouiche, C. Saint-Jore-Dupas, C. Plasson, D. Michaud, and L. Faye. 2010. Plant-specific glycosylation patterns in the context of therapeutic protein production. Plant Biotechnol. J. 8:564-587.
Gonzalez-Olmedo, J.L., Z. Fundora, L.A. Molina, J. Abdulnour, Y. Desjardins, and M. Escalona. 2005. New contributions to propagation of pineapple (Ananas comosus L. Merr) in temporary immersion bioreactors. In Vitro Cell. Dev. Biol.-Plant. 41:87-90.
Gonzalez-Rabade, N., E.G. McGowan, F. Zhou, M.S. McCabe, R. Bock, P.J. Dix, J.C. Gray, and J.K.C. Ma. 2011. Immunogenicity of chloroplast-derived HIV-1 p24 and a p24-Nef fusion protein following subcutaneous and oral administration in mice. Plant Biotechnol. J. 9:629-638.
Gonzalez, D.D., M.V. Mozgovoj, D. Bellido, D.V. Rodriguez, F.M. Fernandez, A. Wigdorovitz, V.G. Parreño, and M.J. Dus Santos. 2010. Evaluation of a bovine rotavirus VP6 vaccine efficacy in the calf model of infection and disease. Veterinary Immunology and Immunopathology. 137:155-160.
Gorret, N., A.K. bin Rosli, S.F. Oppenheim, L.B. Willis, P.A. Lessard, C.K. Rha, and A.J. Sinskey. 2004. Bioreactor culture of oil palm (Elaeis guineensis) and effects of nitrogen source, inoculum size, and conditioned medium on biomass production. Journal of Biotechnology. 108:253-263.
Goswami, S., W. Wang, T. Arakawa, and S. Ohtake. 2013. Developments and challenges for mAb-based therapeutics. Antibodies. 2:452-500.
Gottlieb, T., and T. Ben-Yedidia. Epitope-based approaches to a universal influenza vaccine. Journal of Autoimmunity.
Gould, S.B., R.F. Waller, and G.I. McFadden. 2008. Plastid Evolution. Annual Review of Plant Biology. 59:491-517.
178
Greiner, S., and R. Bock. 2013. Tuning a menage a trois: co-evolution and co-adaptation of nuclear and organellar genomes in plants. BioEssays : news and reviews in molecular, cellular and developmental biology. 35:354-365.
Gribble, K., J. Tingle, V. Sarafis, A. Heaton, and P. Holford. 1998. Position of water in vitrified plants visualised by NMR imaging. Protoplasma. 201:110-114.
Grimes, H.D., and T.K. Hodges. 1990. The Inorganic NO3-: NH4
+ ratio Influences Plant Regeneration and Auxin Sensitivity in Primary Callus Derived from Immature Embryos of Indica Rice (Oryza sativa L.). J. Plant Physiol. 136:362-367.
Guerra, M.P., L.L. Dal Vesco, J.P.H.J. Ducroquet, R.O. Nodari, and M.S.D. Reis. 2001. Somatic embryogenesis in goiabeira serrana: genotype response, auxinic shock and synthetic seeds. Revista Brasileira de Fisiologia Vegetal. 13:117-128.
Hagemann, R. 2004. The Sexual Inheritance of Plant Organelles. In Molecular Biology and Biotechnology of Plant Organelles. H. Daniell and C. Chase, editors. Springer Netherlands. 93-113.
Håkansson, S. 2003. Annual and Perennial crops. Weeds and weed management on arable land: an ecological approach:14-15.
Hanke, G.T., Y. Kimata-Ariga, I. Taniguchi, and T. Hase. 2004. A Post Genomic Characterization of Arabidopsis Ferredoxins. Plant Physiol. 134:255-264.
Hanke, T., and A.J. McMichael. 2000. Design and construction of an experimental HIV-1 vaccine for a year-2000 clinical trial in Kenya. Nat Med. 6:951-955.
Harris, E.H., J.E. Boynton, and N.W. Gillham. 1994. Chloroplast ribosomes and protein synthesis. Microbiological reviews. 58:700.
Häusler, R.E., L. Heinrichs, J. Schmitz, and U.-I. Flügge. 2014. How Sugars Might Coordinate Chloroplast and Nuclear Gene Expression during Acclimation to High Light Intensities. Molecular Plant. 7:1121-1137.
Hawkesford, M., W. Horst, T. Kichey, H. Lambers, J. Schjoerring, I.S. Møller, and P. White. 2012. Chapter 6 - Functions of Macronutrients. In Marschner's Mineral Nutrition of Higher Plants (Third Edition). P. Marschner, editor. Academic Press, San Diego. 135-189.
Hay, M., D.W. Thomas, J.L. Craighead, C. Economides, and J. Rosenthal. 2014. Clinical development success rates for investigational drugs. Nat Biotech. 32:40-51.
Hehle, V.K., M.J. Paul, P.M. Drake, J.K. Ma, and C.J. van Dolleweerd. 2011. Antibody degradation in tobacco plants: a predominantly apoplastic process. BMC Biotechnol. 11:128.
Hein, M.B., Y. Tang, D.A. McLeod, K.D. Janda, and A. Hiatt. 1991. Evaluation of immunoglobulins from plant cells. Biotechnology Progress. 7:455-461.
Hellwig, S., J. Drossard, R.M. Twyman, and R. Fischer. 2004. Plant cell cultures for the production of recombinant proteins. Nat Biotech. 22:1415-1422.
Hiatt, A., R. Caffferkey, and K. Bowdish. 1989. Production of antibodies in transgenic plants. Nature. 342:76-78.
Hiatt, A., and M. Pauly. 2006. Monoclonal antibodies from plants: A new speed record. Proceedings of the National Academy of Sciences. 103:14645-14646.
Hicks, G. 1994. Shoot induction and organogenesis in vitro: A developmental perspective. In Vitro Cellular & Developmental Biology - Plant. 30:10-15.
Higgins, T.J., P.A. O’Brien, D. Spencer, H.E. Schroeder, H. Dove, and M. Freer. 1989. Potential of Transgenic Plants for Improved Amino Acid Supply for Wool Growth. In The Biology of Wool and Hair. G.E. Rogers, P.J. Reis, K.A. Ward, and R.C. Marshall, editors. Springer Netherlands. 441-445.
Hill, J.P., and E.M. Lord. 1990. A Method for Determining Plastochron Indices During Heteroblastic Shoot Growth. American Journal of Botany. 77:1491-1497.
Hirata, N., D. Yonekura, S. Yanagisawa, and K. Iba. 2004. Possible Involvement of the 5′-Flanking Region and the 5′UTR of Plastid accD Gene in NEP-Dependent Transcription. Plant and Cell Physiology. 45:176-186.
179
Hohe, A., and R. Reski. 2002. Optimisation of a bioreactor culture of the moss Physcomitrella patens for mass production of protoplasts. Plant Science. 163:69-74.
Holland, T., M. Sack, T. Rademacher, K. Schmale, F. Altmann, J. Stadlmann, R. Fischer, and S. Hellwig. 2010. Optimal nitrogen supply as a key to increased and sustained production of a monoclonal full-size antibody in BY-2 suspension culture. Biotechnol. Bioeng. 107:278-289.
Hood, E., D. Witcher, S. Maddock, T. Meyer, C. Baszczynski, M. Bailey, P. Flynn, J. Register, L. Marshall, D. Bond, E. Kulisek, A. Kusnadi, R. Evangelista, Z. Nikolov, C. Wooge, R. Mehigh, R. Hernan, W. Kappel, D. Ritland, C. Ping Li, and J. Howard. 1997. Commercial production of avidin from transgenic maize: characterization of transformant, production, processing, extraction and purification. Molecular Breeding. 3:291-306.
Hood, E.E., R. Love, J. Lane, J. Bray, R. Clough, K. Pappu, C. Drees, K.R. Hood, S. Yoon, A. Ahmad, and J.A. Howard. 2007. Subcellular targeting is a key condition for high-level accumulation of cellulase protein in transgenic maize seed. Plant Biotechnol. J. 5:709-719.
Hood, E.E., and S. Woodard. 2005. Commercialization of a protein product from transgenic maize. Natl Agric Biotechnol Council. 17:147-157.
Howard, J.A., Z. Nikolov, and E.E. Hood. 2011. Enzyme Production Systems for Biomass Conversion. In Plant Biomass Conversion. John Wiley & Sons, Inc. 227-253.
Huang, C.Y., M.A. Ayliffe, and J.N. Timmis. 2003. Direct measurement of the transfer rate of chloroplast DNA into the nucleus. Nature. 422:72-76.
Huang, T.-K., and K.A. McDonald. 2012. Bioreactor systems for in vitro production of foreign proteins using plant cell cultures. Biotechnol. Adv. 30:398-409.
Hulse, J.H. 2004. Biotechnologies: past history, present state and future prospects. Trends in Food Science & Technology. 15:3-18.
Hung, C.D., and S.J. Trueman. 2012. Alginate encapsulation of shoot tips and nodal segments for short-term storage and distribution of the eucalypt Corymbia torelliana x C. citriodora. Acta Physiol. Plant. 34:117-128.
Husaini, A.M., Z. Rashid, R.u.R. Mir, and B. Aquil. 2011. Approaches for gene targeting and targeted gene expression in plants. GM Crops. 2:150-162.
Hyunjong, B., D.-S. Lee, and I. Hwang. 2006. Dual targeting of xylanase to chloroplasts and peroxisomes as a means to increase protein accumulation in plant cells. Journal of Experimental Botany. 57:161-169.
Ibrahim, R., and P.C. Debergh. 2001. Factors controlling high efficiency adventitious bud formation and plant regeneration from in vitro leaf explants of roses (Rosa hybrida L.). Scientia Horticulturae. 88:41-57.
Ikeuchi, M., K. Sugimoto, and A. Iwase. 2013. Plant Callus: Mechanisms of Induction and Repression. The Plant Cell Online. 25:3159-3173.
Inka Borchers, A.M., N. Gonzalez-Rabade, and J.C. Gray. 2012. Increased accumulation and stability of rotavirus VP6 protein in tobacco chloroplasts following changes to the 5′ untranslated region and the 5′ end of the coding region. Plant Biotechnol. J. 10:422-434.
Ivanova, M., and J. van Staden. 2008. Effect of ammonium ions and cytokinins on hyperhydricity and multiplication rate of in vitro regenerated shoots of Aloe polyphylla. Plant Cell, Tissue and Organ Culture. 92:227-231.
Ivanova, M., and J. Van Staden. 2009. Nitrogen source, concentration, and NH4+ : NO3
− ratio influence shoot regeneration and hyperhydricity in tissue cultured Aloe polyphylla. Plant Cell, Tissue and Organ Culture. 99:167-174.
Iwarson, S., E. Tabor, H.C. Thomas, P. Snoy, and R.J. Gerety. 1985. Protection against hepatitis B virus infection by immunization with hepatitis B core antigen. Gastroenterology. 88:763-767.
Jablonsky, J., H. Bauwe, and O. Wolkenhauer. 2011. Modeling the Calvin-Benson cycle. BMC Syst Biol. 5:1-13.
Jain, E., and A. Kumar. 2008. Upstream processes in antibody production: Evaluation of critical parameters. Biotechnol. Adv. 26:46-72.
180
Jamal, A., K. Ko, H.-S. Kim, Y.-K. Choo, H. Joung, and K. Ko. 2009. Role of genetic factors and environmental conditions in recombinant protein production for molecular farming. Biotechnol. Adv. 27:914-923.
James, C. 2013. Global Status of Commercialized Biotech/GM Crops. ISAAA Brief 46. Jang, J.C., and J. Sheen. 1994. Sugar sensing in higher plants. The Plant Cell Online. 6:1665-1679. Jansen, R.K., and T.A. Ruhlman. 2012. Plastid Genomes of Seed Plants. In Genomics of Chloroplasts
and Mitochondria. Vol. 35. R. Bock and V. Knoop, editors. Springer Netherlands. 103-126. Jeon, J.Y., J.-S. Kwon, S.T. Kang, B.-R. Kim, Y. Jung, J.G. Han, J.H. Park, and J.K. Hwang. 2014.
Optimization of culture media for large-scale lutein production by heterotrophic Chlorella vulgaris. Biotechnology Progress. 30:736-743.
Jiang, L., and S.S.M. Sun. 2002. Membrane anchors for vacuolar targeting: application in plant bioreactors. Trends Biotechnol. 20:99-102.
Joh, L.D., T. Wroblewski, N.N. Ewing, and J.S. VanderGheynst. 2005. High-level transient expression of recombinant protein in lettuce. Biotechnol. Bioeng. 91:861-871.
Johnson, I.S. 1983. Human Insulin from Recombinant DNA Technology. Science. 219:632-637. Jones, G., and S.K. Talley. 1933. The Viscosity of Aqueous Solutions as a Function of the
Concentration. Journal of the American Chemical Society. 55:624-642. Junker, B.H. 2004. Scale-up methodologies for Escherichia coli and yeast fermentation processes.
Journal of Bioscience and Bioengineering. 97:347-364. Justino, M.C.A., E.C. Araújo, L.-J. van Doorn, C.S. Oliveira, Y.B. Gabbay, J.D.A.P. Mascarenhas, Y.S.
Miranda, S.d.F.S. Guerra, V.B.d. Silva, and A.C. Linhares. 2012. Oral live attenuated human rotavirus vaccine (RotarixTM) offers sustained high protection against severe G9P8 rotavirus gastroenteritis during the first two years of life in Brazilian children. Memórias do Instituto Oswaldo Cruz. 107:846-853.
Kadleček, P., B. Rank, and I. Tichá. 2003. Photosynthesis and photoprotection in Nicotiana tabacum L. in vitro-grown plantlets. J. Plant Physiol. 160:1017-1024.
Kalish, M.L., A. Baldwin, S. Raktham, C. Wasi, C.C. Luo, G. Schochetman, T.D. Mastro, N. Young, S. Vanichseni, H. Rubsamen-Waigmann, and et al. 1995. The evolving molecular epidemiology of HIV-1 envelope subtypes in injecting drug users in Bangkok, Thailand: implications for HIV vaccine trials. AIDS (London, England). 9:851-857.
Kamarajugadda, S., and H. Daniell. 2006. Chloroplast-derived anthrax and other vaccine antigens: their immunogenic and immunoprotective properties.
Kanamoto, H., A. Yamashita, H. Asao, S. Okumura, H. Takase, M. Hattori, A. Yokota, and K.-I. Tomizawa. 2006. Efficient and stable transformation of Lactuca sativa L. cv. Cisco (lettuce) plastids. Transgenic Res. 15:205-217.
Karg, S.R., and P.T. Kallio. 2009. The production of biopharmaceuticals in plant systems. Biotechnol. Adv. 27:879-894.
Kato, A., S. Kawazoe, and Y. Soh. 1978. Viscosity of the Broth of Tobacco Cells in Suspension Culture: Biomass Production of Tobacco Cells (Part IV). Journal of fermentation technology. 56:224-228.
Katsnelson, A., J. Ransom, P. Vermij, and E. Waltz. 2006. News In Brief. Nat Biotech. 24:233-234. Kaul, B., and E.J. Staba. 1968. Dioscorea tissue cultures. 1. Biosynthesis and isolation of diesgenin
from Dioscorea deltoidea callus and suspension cells. Lloydia. 31:171-179. Kennedy, M.J. 1991. The evolution of the word ‘biotechnology’. Trends Biotechnol. 9:218-220. Kevers, C., T. Franck, R.J. Strasser, J. Dommes, and T. Gaspar. 2004. Hyperhydricity of
Micropropagated Shoots: A Typically Stress-induced Change of Physiological State. Plant Cell, Tissue and Organ Culture. 77:181-191.
Khoudi, H., S. Laberge, J.-M. Ferullo, R. Bazin, A. Darveau, Y. Castonguay, G. Allard, R. Lemieux, and L.-P. Vézina. 1999. Production of a diagnostic monoclonal antibody in perennial alfalfa plants. Biotechnol. Bioeng. 64:135-143.
181
Kieran, P., D. Malone, and P. MacLoughlin. 2000. Effects of Hydrodynamic and Interfacial Forces on Plant Cell Suspension Systems. Adv. Biochem. Eng. Biotechnol. 67:139-177.
Kieran, P.M., P.F. MacLoughlin, and D.M. Malone. 1997. Plant cell suspension cultures: some engineering considerations. Journal of Biotechnology. 59:39-52.
Kim, D.-I., H. Pedersen, and C.-K. Chin. 1991. Development of process strategies for berberine production in plant cell suspension cultures. Journal of Biotechnology. 21:201-207.
Kim, M., D. Christopher, and J. Mullet. 1993. Direct evidence for selective modulation of psbA, rpoA, rbcL and 16S RNA stability during barley chloroplast development. Plant Mol.Biol. 22:447-463.
Kim, M., and J. Park. 2002. High Frequency Plant Regeneration of Garlic (Allium sativum L.) Calli Immobilized in Calcium Alginate Gel. Biotechnology and Bioprocess Engineering. 7:206-211.
Klein, R., and J. Mullet. 1987. Control of gene expression during higher plant chloroplast biogenesis. Protein synthesis and transcript levels of psbA, psaA-psaB, and rbcL in dark-grown and illuminated barley seedlings. Journal of Biological Chemistry. 262:4341-4348.
Klingenberg, P. 1984. A. T. Bull, G. Holt und M. D. Lilly: Biotechnology — international trends and perspectives. 84 Seiten. OECD Publ., Paris 1982. Preis: 28,— DM. Food / Nahrung. 28:900-900.
Klughammer, C., and U. Schreiber. 1994. An improved method, using saturating light pulses, for the determination of photosystem I quantum yield via P700+-absorbance changes at 830 nm. Planta. 192:261-268.
Knoblauch, M., J.M. Hibberd, J.C. Gray, and A.J.E. van Bel. 1999. A galinstan expansion femtosyringe for microinjection of eukaryotic organelles and prokaryotes. Nat Biotech. 17:906-909.
Ko, K., M.H. Ahn, M. Song, Y.K. Choo, H.S. Kim, K. Ko, and H. Joung. 2008. Glyco-engineering of biotherapeutic proteins in plants. Molecules and cells. 25:494-503.
Ko, K., R. Brodzik, and Z. Steplewski. 2009. Production of Antibodies in Plants: Approaches and Perspectives. In Plant-produced Microbial Vaccines. Vol. 332. A. Karasev, editor. Springer Berlin Heidelberg. 55-78.
Ko, K., and H. Koprowski. 2005. Plant biopharming of monoclonal antibodies. Virus Research. 111:93-100.
Ko, K., Y. Tekoah, P.M. Rudd, D.J. Harvey, R.A. Dwek, S. Spitsin, C.A. Hanlon, C. Rupprecht, B. Dietzschold, M. Golovkin, and H. Koprowski. 2003. Function and glycosylation of plant-derived antiviral monoclonal antibody. Proceedings of the National Academy of Sciences. 100:8013-8018.
Kofer, W., C. Eibl, K. Steinmüller, and H.-U. Koop. 1998. PEG-mediated plastid transformation in higher plants. In Vitro Cellular & Developmental Biology - Plant. 34:303-309.
Kohler, G., and C. Milstein. 1975. Continuous cultures of fused cells secreting antibody of predefined specificity. Nature. 256:495-497.
Koprowski, H. 2005. Vaccines and sera through plant biotechnology. Vaccine. 23:1757-1763. Kota, M., H. Daniell, S. Varma, S.F. Garczynski, F. Gould, and W.J. Moar. 1999. Overexpression of the
Bacillus thuringiensis (Bt) Cry2Aa2 protein in chloroplasts confers resistance to plants against susceptible and Bt-resistant insects. Proceedings of the National Academy of Sciences. 96:1840-1845.
Kovtun, Y., and J. Daie. 1995. End-Product Control of Carbon Metabolism in Culture-grown Sugar Beet Plants (Molecular and Physiological Evidence on Accelerated Leaf Development and Enhanced Gene Expression). Plant Physiol. 108:1647-1656.
Koya, V., M. Moayeri, S.H. Leppla, and H. Daniell. 2005. Plant-Based Vaccine: Mice Immunized with Chloroplast-Derived Anthrax Protective Antigen Survive Anthrax Lethal Toxin Challenge. Infection and Immunity. 73:8266-8274.
182
Kozai, T. 1991. Photoautotrophic micropropagation. In Vitro Cellular & Developmental Biology - Plant. 27:47-51.
Kozai, T., K. Iwabuchi, K. Watanabe, and I. Watanabe. 1991. Photoautotrophic and photomixotrophic growth of strawberry plantlets in vitro and changes in nutrient composition of the medium. Plant Cell Tissue Organ Cult. 25:107-115.
Kozai, T., and C. Kubota. 2001. Developing a photoautotrophic micropropagation system for woody plants. J. Plant Res. 114:525-537.
Kubota, C., M. Ezawa, T. Kozai, and S.B. Wilson. 2002. In Situ Estimation of Carbon Balance of In Vitro Sweet Potato and Tomato Plantlets Cultured with Varying Initial Sucrose Concentrations in the Medium. Journal of the American Society for Horticultural Science. 127:963-970.
Kumar, M.B.A., V. Vakeswaran, and V. Krishnasamy. 2005. Enhancement of synthetic seed conversion to seedlings in hybrid rice. Plant Cell, Tissue and Organ Culture. 81:97-100.
Kumar, S., A. Dhingra, and H. Daniell. 2004. Plastid-expressed betaine aldehyde dehydrogenase gene in carrot cultured cells, roots, and leaves confers enhanced salt tolerance. Plant Physiol. 136:2843-2854.
Kumar, S., F.M. Hahn, E. Baidoo, T.S. Kahlon, D.F. Wood, C.M. McMahan, K. Cornish, J.D. Keasling, H. Daniell, and M.C. Whalen. 2012. Remodeling the isoprenoid pathway in tobacco by expressing the cytoplasmic mevalonate pathway in chloroplasts. Metabolic engineering. 14:19-28.
Kumar Tewari, R., P. Kumar, and P. Nand Sharma. 2006. Magnesium deficiency induced oxidative stress and antioxidant responses in mulberry plants. Scientia horticulturae. 108:7-14.
Kumar, V., M.M. Naidu, and G.A. Ravishankar. 2006. Developments in coffee biotechnology - in vitro plant propagation and crop improvement. Plant Cell Tissue Organ Cult. 87:49-65.
Kuroda, H., and P. Maliga. 2001a. Complementarity of the 16S rRNA penultimate stem with sequences downstream of the AUG destabilizes the plastid mRNAs. Nucleic Acids Res. 29:970-975.
Kuroda, H., and P. Maliga. 2001b. Sequences downstream of the translation initiation codon are important determinants of translation efficiency in chloroplasts. Plant Physiol. 125:430-436.
Kusnadi, A.R., Z.L. Nikolov, and J.A. Howard. 1997. Production of recombinant proteins in transgenic plants: Practical considerations. Biotechnol. Bioeng. 56:473-484.
Kutschera, U., and K.J. Niklas. 2013. Cell division and turgor-driven stem elongation in juvenile plants: A synthesis. Plant Science. 207:45-56.
Kuystermans, D., B. Krampe, H. Swiderek, and M. Al-Rubeai. 2007. Using cell engineering and omic tools for the improvement of cell culture processes. Cytotechnology. 53:3-22.
Kwok, K.H., P. Tsoulpha, and P.M. Doran. 1992. Limitations associated with conductivity measurement for monitoring growth in plant tissue culture. Plant Cell, Tissue and Organ Culture. 29:93-99.
Kwon, J.Y., Y.S. Yang, S.H. Cheon, H.J. Nam, G.H. Jin, and D.I. Kim. 2013. Bioreactor engineering using disposable technology for enhanced production of hCTLA4Ig in transgenic rice cell cultures. Biotechnol Bioeng. 110:2412-2424.
Ladygin, V., N. Bondarev, G. Semenova, A. Smolov, O. Reshetnyak, and A. Nosov. 2008. Chloroplast ultrastructure, photosynthetic apparatus activities and production of steviol glycosides in Stevia rebaudiana in vivo and in vitro. Biol. Plant. 52:9-16.
Lai, H., and Q. Chen. 2012. Bioprocessing of plant-derived virus-like particles of Norwalk virus capsid protein under current Good Manufacture Practice regulations. Plant Cell Reports. 31:573-584.
Lau, O.S., and S.S.M. Sun. 2009. Plant seeds as bioreactors for recombinant protein production. Biotechnol. Adv. 27:1015-1022.
Leader, B., Q.J. Baca, and D.E. Golan. 2008. Protein therapeutics: a summary and pharmacological classification. Nat Rev Drug Discov. 7:21-39.
183
Lee, M., and Y. Yang. 2006. Transient Expression Assay by Agroinfiltration of Leaves. In Arabidopsis Protocols. Vol. 323. J. Salinas and J. Sanchez-Serrano, editors. Humana Press. 225-229.
Lee, S.M., K. Kang, H. Chung, S.H. Yoo, X.M. Xu, S.B. Lee, J.J. Cheong, H. Daniell, and M. Kim. 2006. Plastid transformation in the monocotyledonous cereal crop, rice (Oryza sativa) and transmission of transgenes to their progeny. Molecules and cells. 21:401-410.
Lico, C., A. Desiderio, S. Banchieri, and E. Benvenuto. 2005. Plants as biofactories: Production of pharmaceutical recombinant proteins. In Proceedings of the International Congress “In the Wake of the Double Helix: From the Green Revolution to the Gene Revolution. 577-593.
Lim, S., J. Seon, K. Paek, B. Han, and S. Son. 1997. Development of pilot scale process for mass production of Lilium bulblets in vitro. In International Symposium on Biotechnology of Tropical and Subtropical Species Part 2 461. 237-242.
Lin, M.T., A. Occhialini, P.J. Andralojc, M.A. Parry, and M.R. Hanson. 2014. A faster Rubisco with potential to increase photosynthesis in crops. Nature. 513:547-550.
Liu, C.W., C.C. Lin, J.J.W. Chen, and M.J. Tseng. 2007. Stable chloroplast transformation in cabbage (Brassica oleracea L. var. capitata L.) by particle bombardment. Plant Cell Reports. 26:1733-1744.
Liu, C.W., C.C. Lin, J.C. Yiu, J.J.W. Chen, and M.J. Tseng. 2008. Expression of a Bacillus thuringiensis toxin (cry1Ab) gene in cabbage (Brassica oleracea L. var. capitata L.) chloroplasts confers high insecticidal efficacy against Plutella xylostella. Theor. Appl. Genet. 117:75-88.
Loesche, W.J. 1986. Role of Streptococcus mutans in human dental decay. Microbiological Reviews. 50:353-380.
Lorenzo, J.C., B.L. Gonzalez, M. Escalona, C. Teisson, P. Espinosa, and C. Borroto. 1998. Sugarcane shoot formation in an improved temporary immersion system. Plant Cell Tissue Organ Cult. 54:197-200.
Lossl, A., K. Bohmert, H. Harloff, C. Eibl, S. Muhlbauer, and H.U. Koop. 2005. Inducible trans-activation of plastid transgenes: Expression of the R. eutropha phb operon in transplastomic tobacco. Plant and Cell Physiology. 46:1462-1471.
Lutz, K.A., A. Azhagiri, and P. Maliga. 2011. Transplastomics in Arabidopsis: Progress Toward Developing an Efficient Method. In Chloroplast Research in Arabidopsis. Vol. 774. R.P. Jarvis, editor. Humana Press. 133-147.
Lutz, K.A., J.E. Knapp, and P. Maliga. 2001. Expression of bar in the plastid genome confers herbicide resistance. Plant Physiol. 125:1585-1590.
Lymbery, P. 2014. Farmageddon: The True Cost of Cheap Meat. Bloomsbury Publishing. Lynd, L.R., C.E. Wyman, and T.U. Gerngross. 1999. Biocommodity Engineering. Biotechnology
Progress. 15:777-793. Ma, J.K.C., E. Barros, R. Bock, P. Christou, P.J. Dale, P.J. Dix, R. Fischer, J. Irwin, R. Mahoney, M.
Pezzotti, S. Schillberg, P. Sparrow, E. Stoger, and R.M. Twyman. 2005a. Molecular farming for new drugs and vaccines. EMBO reports. 6:593-599.
Ma, J.K.C., P. Christou, R. Chikwamba, H. Haydon, M. Paul, M.P. Ferrer, S. Ramalingam, E. Rech, E. Rybicki, A. Wigdorowitz, D.-C. Yang, and H. Thangaraj. 2013. Realising the value of plant molecular pharming to benefit the poor in developing countries and emerging economies. Plant Biotechnol. J. 11:1029-1033.
Ma, J.K.C., P.M.W. Drake, D. Chargelegue, P. Obregon, and A. Prada. 2005b. Antibody processing and engineering in plants, and new strategies for vaccine production. Vaccine. 23:1814-1818.
Ma, J.K.C., and M.B. Hein. 1995. Immunotherapeutic potential of antibodies produced in plants. Trends Biotechnol. 13:522-527.
Ma, J.K.C., B.Y. Hikmat, K. Wycoff, N.D. Vine, D. Chargelegue, L. Yu, M.B. Hein, and T. Lehner. 1998. Characterization of a recombinant plant monoclonal secretory antibody and preventive immunotherapy in humans. Nat Med. 4:601-606.
184
Ma, J.K.C., T. Lehner, P. Stabila, C.I. Fux, and A. Hiatt. 1994. Assembly of monoclonal antibodies with IgG1 and IgA heavy chain domains in transgenic tobacco plants. European Journal of Immunology. 24:131-138.
Ma, Z., C. Cooper, H.-J. Kim, and D. Janick-Buckner. 2009. A Study of Rubisco through Western Blotting and Tissue Printing Techniques. CBE Life Sciences Education. 8:140-146.
MacLoughlin, P.F., D.M. Malone, J.T. Murtagh, and P.M. Kieran. 1998. The effects of turbulent jet flows on plant cell suspension cultures. Biotechnol. Bioeng. 58:595-604.
Magy, B., J. Tollet, R. Laterre, M. Boutry, and C. Navarre. 2014. Accumulation of secreted antibodies in plant cell cultures varies according to the isotype, host species and culture conditions. Plant Biotechnol. J. 12:457-467.
Majumdar, S.R. 1996. Pneumatic Systems: Principles and Maintenance. McGraw-Hill. Makoff, A.J., S.P. Ballantine, A.E. Smallwood, and N.F. Fairweather. 1989. Expression of Tetanus
Toxin Fragment C in E. coli: Its Purification and Potential Use as a Vaccine. Nat Biotech. 7:1043-1046.
Maliga, P. 2002. Engineering the plastid genome of higher plants. Curr Opin Plant Biol. 5:164-172. Maliga, P. 2003. Progress towards commercialization of plastid transformation technology. Trends
Biotechnol. 21:20-28. Maliga, P. 2004. Plastid transformation in higher plants. Annual Review of Plant Biology. 55:289-313. Maliga, P., and R. Bock. 2011. Plastid Biotechnology: Food, Fuel, and Medicine for the 21st Century.
Plant Physiol. 155:1501-1510. Martin, S.M., and D. Rose. 1976. Growth of plant cell (Ipomoea) suspension cultures at controlled pH
levels. Canadian Journal of Botany. 54:1264-1270. Martin, W., T. Rujan, E. Richly, A. Hansen, S. Cornelsen, T. Lins, D. Leister, B. Stoebe, M. Hasegawa,
and D. Penny. 2002. Evolutionary analysis of Arabidopsis, cyanobacterial, and chloroplast genomes reveals plastid phylogeny and thousands of cyanobacterial genes in the nucleus. Proc. Natl. Acad. Sci. U. S. A. 99:12246-12251.
Martine, G., H. Philippe, and S. Myriam. 2009. Biosafety considerations associated with molecular farming in genetically modified plants. Journal of Medicinal Plants Research. 3:825-838.
Masclaux-Daubresse, C., F. Daniel-Vedele, J. Dechorgnat, F. Chardon, L. Gaufichon, and A. Suzuki. 2010. Nitrogen uptake, assimilation and remobilization in plants: challenges for sustainable and productive agriculture. Annals of Botany. 105:1141-1157.
Mason, H.S., H. Warzecha, T. Mor, and C.J. Arntzen. 2002. Edible plant vaccines: applications for prophylactic and therapeutic molecular medicine. Trends in Molecular Medicine. 8:324-329.
Maxwell, K., and G.N. Johnson. 2000. Chlorophyll fluorescence—a practical guide. Journal of Experimental Botany. 51:659-668.
McCabe, M.S., M. Klaas, N. Gonzalez-Rabade, M. Poage, J.A. Badillo-Corona, F. Zhou, D. Karcher, R. Bock, J.C. Gray, and P.J. Dix. 2008. Plastid transformation of high-biomass tobacco variety Maryland Mammoth for production of human immunodeficiency virus type 1 (HIV-1) p24 antigen. Plant Biotechnol. J. 6:914-929.
McDonald, K.A., and A.P. Jackman. 1989. Bioreactor studies of growth and nutrient utilization in alfalfa suspension cultures. Plant Cell Reports. 8:455-458.
Meijer, J.J., H.J.G. ten Hoopen, K.C.A.M. Luyben, and K.R. Libbenga. 1993. Effects of hydrodynamic stress on cultured plant cells: A literature survey. Enzyme and Microbial Technology. 15:234-238.
Menke, W. 1962. Structure and Chemistry of Plastids. Annual Review of Plant Physiology. 13:27-44. Menkhaus, T.J., Y. Bai, C. Zhang, Z.L. Nikolov, and C.E. Glatz. 2004. Considerations for the Recovery of
Recombinant Proteins from Plants. Biotechnology Progress. 20:1001-1014. Menkhaus, T.J., and C.E. Glatz. 2005. Antibody Capture from Corn Endosperm Extracts by Packed
Bed and Expanded Bed Adsorption. Biotechnology Progress. 21:473-485. Merchuk, J. 1991. Shear effects on suspended cells. In Bioreactor Systems and Effects. Vol. 44.
Springer Berlin Heidelberg. 65-95.
185
Merlin, M., E. Gecchele, S. Capaldi, M. Pezzotti, and L. Avesani. 2014. Comparative Evaluation of Recombinant Protein Production in Different Biofactories: The Green Perspective. BioMed research international. 2014.
Metz, B., W. Tilstra, R. van der Put, N. Spruit, J. van den Ijssel, J. Robert, C. Hendriksen, and G. Kersten. 2013. Physicochemical and immunochemical assays for monitoring consistent production of tetanus toxoid. Biologicals. 41:231-237.
Meyer, C., and M. Stitt. 2001. Nitrate Reduction and signalling. In Plant Nitrogen. P. Lea and J.-F. Morot-Gaudry, editors. Springer Berlin Heidelberg. 37-59.
Meyers, A., E. Chakauya, E. Shephard, F.L. Tanzer, J. Maclean, A. Lynch, A.-L. Williamson, and E.P. Rybicki. 2008. Expression of HIV-1 antigens in plants as potential subunit vaccines. BMC Biotechnol.
Michoux, F., N. Ahmad, A. Hennig, P. Nixon, and H. Warzecha. 2013. Production of leafy biomass using temporary immersion bioreactors: an alternative platform to express proteins in transplastomic plants with drastic phenotypes. Planta. 237:903-908.
Michoux, F., N. Ahmad, J. McCarthy, and P.J. Nixon. 2011. Contained and high-level production of recombinant protein in plant chloroplasts using a temporary immersion bioreactor. Plant Biotechnol. J. 9:575-584.
Mishra, N., P.N. Gupta, K. Khatri, A.K. Goyal, and S.P. Vyas. 2008. Edible vaccines: A new approach to oral immunization. Indian J Biotechnol. 7:283-294.
Miyazaki, J., B. Tan, and S. Errington. 2010. Eradication of endophytic bacteria via treatment for axillary buds of Petunia hybrida using Plant Preservative Mixture (PPMTM). Plant Cell Tiss Organ Cult. 102:365-372.
Møller, S.G., J. Maple, and D. Gargano. 2014. Biogenesis of Chloroplasts. In The Structural Basis of Biological Energy Generation. Springer. 435-449.
Moon, K.H., H. Honda, and T. Kobayashi. 1999. Development of a bioreactor suitable for embryogenic rice callus culture. Journal of Bioscience and Bioengineering. 87:661-665.
Mooney, B.P. 2009. The second green revolution? Production of plant-based biodegradable plastics. The Biochemical journal. 418:219-232.
Mooney, M. 1951. The viscosity of a concentrated suspension of spherical particles. Journal of Colloid Science. 6:162-170.
Mordocco, A.M., J.A. Brumbley, and P. Lakshmanan. 2009. Development of a temporary immersion system (RITA) for mass production of sugarcane (Saccharum spp. interspecific hybrids). In Vitro Cell. Dev. Biol.-Plant. 45:450-457.
Morikawa, Y., D.J. Hockley, M.V. Nermut, and I.M. Jones. 2000. Roles of matrix, p2, and N-terminal myristoylation in human immunodeficiency virus type 1 Gag assembly. J Virol. 74:16-23.
Munetaka, S. 1999. Organogenesis in vitro. Current Opinion in Plant Biology. 2:61-64. Munro, G.H., P. Evans, S. Todryk, P. Buckett, C.G. Kelly, and T. Lehner. 1993. A protein fragment of
streptococcal cell surface antigen I/II which prevents adhesion of Streptococcus mutans. Infection and Immunity. 61:4590-4598.
Murashige, T. 1977. Plant cell and organ cultures as horticultural practices. In Symposium on Tissue Culture for Horticultural Purposes 78. 17-30.
Murashige, T., and F. Skoog. 1962. A Revised Medium for Rapid Growth and Bio Assays with Tobacco Tissue Cultures. Physiologia Plantarum. 15:473-497.
Murthy, B.N.S., S.J. Murch, and P. Saxena. 1998. Thidiazuron: A potent regulator of in vitro plant morphogenesis. In Vitro Cellular & Developmental Biology - Plant. 34:267-275.
Nagakubo, T., A. Nagasawa, and H. Ohkawa. 1993. Micropropagation of garlic through in vitro bulblet formation. Plant Cell, Tissue and Organ Culture. 32:175-183.
Nagamori, E., H. Honda, and T. Kobayashi. 1999. Release of embryogenic carrot cells with high regeneration potency from immobilized alginate beads. Journal of Bioscience and Bioengineering. 88:226-228.
186
Nagels, B., K. Weterings, N. Callewaert, and E.J.M. Van Damme. 2012. Production of Plant Made Pharmaceuticals: From Plant Host to Functional Protein. Crit. Rev. Plant Sci. 31:148-180.
Naik, S.K., and P.K. Chand. 2006. Nutrient-alginate encapsulation of in vitro nodal segments of pomegranate (Punica granatum L.) for germplasm distribution and exchange. Scientia Horticulturae. 108:247-252.
Cantillana. 2011. Thermo-photo-bioreactor and method for the culture and mass micropropagation of Deschampsia antarctica in vitro. Google Patents.
Neales, T.F., and L.D. Incoll. 1968. The control of leaf photosynthesis rate by the level of assimilate concentration in the leaf: A review of the hypothesis. Bot. Rev. 34:107-125.
Nelson, D.L., A.L. Lehninger, and M.M. Cox. 2008. Lehninger principles of biochemistry. Macmillan. Neve, M., M. Loose, A. Jacobs, H. Houdt, B. Kaluza, U. Weidle, M. Montagu, and A. Depicker. 1993.
Assembly of an antibody and its derived antibody fragment in Nicotiana and Arabidopsis. Transgenic Res. 2:227-237.
Nguyen, T.T., G. Nugent, T. Cardi, and P.J. Dix. 2005. Generation of homoplasmic plastid transformants of a commercial cultivar of potato (Solanum tuberosum L.). Plant Science. 168:1495-1500.
Nhut, D.T., T. Takamura, H. Watanabe, K. Okamoto, and M. Tanaka. 2003. Responses of strawberry plantlets cultured in vitro under superbright red and blue light-emitting diodes (LEDs). Plant Cell, Tissue and Organ Culture. 73:43-52.
Nicholson, L., P. Gonzalez-Melendi, C. Van Dolleweerd, H. Tuck, Y. Perrin, J.K.C. Ma, R. Fischer, P. Christou, and E. Stoger. 2005. A recombinant multimeric immunoglobulin expressed in rice shows assembly-dependent subcellular localization in endosperm cells. Plant Biotechnol. J. 3:115-127.
Niedz, R.P. 1998. Using Isothiazolone Biocides to Control Microbial and Fungal Contaminants in Plant Tissue Cultures. HortTechnology. 8:598-601.
Niedz, R.P., and M.G. Bausher. 2002. Control of in vitro contamination of explants from greenhouse- and field-grown trees. In Vitro Cellular & Developmental Biology - Plant. 38:468-471.
Nikolov, Z., and D. Hammes. 2002. Production of recombinant proteins from transgenic crops. In Plants as Factories for Protein Production. Springer. 159-174.
Nikolov, Z.L., J.T. Regan, L.F. Dickey, and S.L. Woodard. 2008. Purification of Antibodies From Transgenic Plants. In Process Scale Purification of Antibodies. John Wiley & Sons, Inc. 387-406.
Nikolov, Z.L., and S.L. Woodard. 2004. Downstream processing of recombinant proteins from transgenic feedstock. Current Opinion in Biotechnology. 15:479-486.
North, J.J., P.A. Ndakidemi, and C.P. Laubscher. 2011. Effects of various media compositions on the in vitro germination and discoloration of immature embryos of bird of paradise (Strelitzia reginae). Plant Omics. 4:100-113.
Novitsky, V., P. Gilbert, T. Peter, M.F. McLane, S. Gaolekwe, N. Rybak, I. Thior, T. Ndung'u, R. Marlink, T.H. Lee, and M. Essex. 2003. Association between Virus-Specific T-Cell Responses and Plasma Viral Load in Human Immunodeficiency Virus Type 1 Subtype C Infection. Journal of Virology. 77:882-890.
Novitsky, V., N. Rybak, M.F. McLane, P. Gilbert, P. Chigwedere, I. Klein, S. Gaolekwe, S.Y. Chang, T. Peter, I. Thior, T. Ndung'u, F. Vannberg, B.T. Foley, R. Marlink, T.H. Lee, and M. Essex. 2001. Identification of Human Immunodeficiency Virus Type 1 Subtype C Gag-, Tat-, Rev-, and Nef-Specific Elispot-Based Cytotoxic T-Lymphocyte Responses for AIDS Vaccine Design. Journal of Virology. 75:9210-9228.
Nugent, G.D., S. Coyne, T.T. Nguyen, T.A. Kavanagh, and P.J. Dix. 2006. Nuclear and plastid transformation of Brassica oleracea var. botrytis (cauliflower) using PEG-mediated uptake of DNA into protoplasts. Plant Science. 170:135-142.
187
Obembe, O.O., J.O. Popoola, S. Leelavathi, and S.V. Reddy. 2011. Advances in plant molecular farming. Biotechnol. Adv. 29:210-222.
Oey, M., M. Lohse, B. Kreikemeyer, and R. Bock. 2009. Exhaustion of the chloroplast protein synthesis capacity by massive expression of a highly stable protein antibiotic. Plant J. 57:436-445.
Ohtani, T., G. Galili, J. Wallace, G. Thompson, and B. Larkins. 1991. Normal and lysine-containing zeins are unstable in transgenic tobacco seeds. Plant Mol.Biol. 16:117-128.
Okamoto, K., T. Yanagi, S. Takita, M. Tanaka, T. Higuchi, Y. Ushida, and H. Watanabe. 1996. Development of plant growth apparatus using blue and red LED as artificial light source. In International Symposium on Plant Production in Closed Ecosystems 440. 111-116.
Olmos, E., and E. Hellın. 1998. Ultrastructural differences of hyperhydric and normal leaves from regenerated carnation plants. Scientia Horticulturae. 75:91-101.
Olmos, E., A. Piqueras, J. Ramón Martınez-Solano, and E. Hellın. 1997. The subcellular localization of peroxidase and the implication of oxidative stress in hyperhydrated leaves of regenerated carnation plants. Plant Science. 130:97-105.
Onishi, N., Y. Sakamoto, and T. Hirosawa. 1994. Synthetic seeds as an application of mass production of somatic embryos. Plant Cell Tissue Organ Cult. 39:137-145.
Onodera, R. 1993. Methionine and lysine metabolism in the rumen and the possible effects of their metabolites on the nutrition and physiology of ruminants. Amino Acids. 5:217-232.
Orenstein, W.A., W. Atkinson, D. Mason, and R.H. Bernier. 1990. Barriers to vaccinating preschool children. Journal of health care for the poor and underserved. 1:315-330.
Osteryoung, K.W., and K.A. Pyke. 2014. Division and Dynamic Morphology of Plastids. Annual Review of Plant Biology. 65:443-472.
Outchkourov, N.S., B. Rogelj, B. Strukelj, and M.A. Jongsma. 2003. Expression of Sea Anemone Equistatin in Potato. Effects of Plant Proteases on Heterologous Protein Production. Plant Physiol. 133:379-390.
Ovečka, M., M. Bobák, and J. Šamaj. 1997. Development of shoot primordia in tissue culture of Papaver somniferum L. Biol. Plant. 39:499-506.
Owen, H.R., D. Wengerd, and A.R. Miller. 1991. Culture medium pH is influenced by basal medium, carbohydrate source, gelling agent, activated-charcoal, and medium storage method. Plant Cell Reports. 10:583-586.
Palmer, J.D. 1983. Chloroplast DNA exists in two orientations. Nature. 301:92-93. Palmer, J.D. 1985. Comparative organization of chloroplast genomes. Annu. Rev. Genet. 19:325-354. Parashar, U.D., C.J. Gibson, J.S. Bresee, and R.I. Glass. 2006. Rotavirus and severe childhood diarrhea.
Emerging infectious diseases. 12:304-306. Park, Y.-G., S.-J. Kim, Y.-M. Kang, H.-Y. Jung, D. Prasad, S.-W. Kim, Y.-G. Chung, and M.-S. Choi. 2004a.
Production of ginkgolides and bilobalide from optimized the <i>Ginkgo biloba</i> cell culture. Biotechnology and Bioprocess Engineering. 9:41-46.
Park, Y.-G., S.-J. Kim, Y.-M. Kang, H.-Y. Jung, D. Prasad, S.-W. Kim, Y.-G. Chung, and M.-S. Choi. 2004b. Production of ginkgolides and bilobalide from optimized the Ginkgo biloba cell culture. Biotechnology and Bioprocess Engineering. 9:41-46.
Parmenter, D.L., J.G. Boothe, and M.M. Moloney. 1996. Production and Purification of Recombinant Hirudin from Plant Seeds. Transgenic plants: a production system for industrial and pharmaceutical proteins:261.
Parra, G., K. Bradnam, A.B. Rose, and I. Korf. 2011. Comparative and functional analysis of intron-mediated enhancement signals reveals conserved features among plants. Nucleic Acids Res. 39:5328-5337.
Patel, A.V., I. Pusch, G. Mix-Wagner, and K.D. Vorlop. 2000. A novel encapsulation technique for the production of artificial seeds. Plant Cell Reports. 19:868-874.
Paul, M.J., and T.K. Pellny. 2003. Carbon metabolite feedback regulation of leaf photosynthesis and development. Journal of Experimental Botany. 54:539-547.
188
Percy, J.R., M.E. Percy, and R. Baumal. 1976. Assembly of three major subclasses of mouse immunoglobulin G: a theoretical model for covalent assembly in vivo. Can J Biochem. 54:688-698.
Perveen, S., and M. Anis. 2014. Encapsulation of internode regenerated adventitious shoot buds of Indian Siris in alginate beads for temporary storage and twofold clonal plant production. Acta Physiol. Plant. 36:2067-2077.
Petrović, A. 2013. Effect of nutrient starvation on some aspects of nitrogen metabolism in substrate-grown strawberry plantings cv. Nyoho. Ratarstvo i povrtarstvo. 50:24-30.
Petruccelli, S., M.S. Otegui, F. Lareu, O. Tran Dinh, A.C. Fitchette, A. Circosta, M. Rumbo, M. Bardor, R. Carcamo, and V. Gomord. 2006. A KDEL‐tagged monoclonal antibody is efficiently retained in the endoplasmic reticulum in leaves, but is both partially secreted and sorted to protein storage vacuoles in seeds. Plant Biotechnol. J. 4:511-527.
Piccioni, E. 1997. Plantlets from encapsulated micropropagated buds of M.26 apple rootstock. Plant Cell, Tissue and Organ Culture. 47:255-260.
Pickering, F., and P. Reis. 1993. Effects of abomasal supplements of methionine on wool growth of grazing sheep. Australian Journal of Experimental Agriculture. 33:7-12.
Picoli, E.A.T., W.C. Otoni, M.r.L. Figueira, S.M.B. Carolino, R.S. Almeida, E.A.M. Silva, C.R. Carvalho, and E.P.B. Fontes. 2001. Hyperhydricity in in vitro eggplant regenerated plants: structural characteristics and involvement of BiP (Binding Protein). Plant Science. 160:857-868.
Pillay, V., H.K. Gan, and A.M. Scott. 2011. Antibodies in oncology. New Biotechnology. 28:518-529. Pogue, G.P., J.A. Lindbo, S.J. Garger, and W.P. Fitzmaurice. 2002. Making an ally from an enemy:
Plant Virology and the New Agriculture. Annual Review of Phytopathology. 40:45-74. Popoff, M.R. 1995. Ecology of Neurotoxigenic Strains of Clostridia. In Clostridial Neurotoxins. Vol.
195. C. Montecucco, editor. Springer Berlin Heidelberg. 1-29. Pospóšilová, J., I. Tichá, P. Kadleček, D. Haisel, and Š. Plzáková. 1999. Acclimatization of
Micropropagated Plants to Ex Vitro Conditions. Biol. Plant. 42:481-497. Potenza, C., L. Aleman, and C. Sengupta-Gopalan. 2004. Targeting transgene expression in research,
agricultural, and environmental applications: Promoters used in plant transformation. In Vitro Cellular & Developmental Biology - Plant. 40:1-22.
Qiu, X., G. Wong, J. Audet, A. Bello, L. Fernando, J.B. Alimonti, H. Fausther-Bovendo, H. Wei, J. Aviles, E. Hiatt, A. Johnson, J. Morton, K. Swope, O. Bohorov, N. Bohorova, C. Goodman, D. Kim, M.H. Pauly, J. Velasco, J. Pettitt, G.G. Olinger, K. Whaley, B. Xu, J.E. Strong, L. Zeitlin, and G.P. Kobinger. 2014. Reversion of advanced Ebola virus disease in nonhuman primates with ZMapp. Nature. advance online publication.
Rafiqul, M., I. Khan, A. Ceriotti, L. Tabe, A. Aryan, W. McNabb, A. Moore, S. Craig, D. Spencer, and T.V. Higgins. 1996. Accumulation of a sulphur-rich seed albumin from sunflower in the leaves of transgenic subterranean clover (Trifolium subterraneum L.). Transgenic Res. 5:179-185.
Ragauskas, A.J., C.K. Williams, B.H. Davison, G. Britovsek, J. Cairney, C.A. Eckert, W.J. Frederick, J.P. Hallett, D.J. Leak, C.L. Liotta, J.R. Mielenz, R. Murphy, R. Templer, and T. Tschaplinski. 2006. The Path Forward for Biofuels and Biomaterials. Science. 311:484-489.
Rai, M.K., V.S. Jaiswal, and U. Jaiswal. 2008. Encapsulation of shoot tips of guava (Psidium guajava L.) for short-term storage and germplasm exchange. Scientia Horticulturae. 118:33-38.
Ramage, C.M., and R.R. Williams. 2002. Inorganic nitrogen requirements during shoot organogenesis in tobacco leaf discs. Journal of Experimental Botany. 53:1437-1443.
Ramírez, N., P. Oramas, M. Ayala, M. Rodríguez, M. Pérez, and J. Gavilondo. 2001. Expression and long-term stability of a recombinant single-chain Fv antibody fragment in transgenic Nicotiana tabacum seeds. Biotechnol. Lett. 23:47-49.
Raven, J.A., B. Wollenweber, and L.L. Handley. 1992. A Comparison of Ammonium and Nitrate as Nitrogen Sources for Photolithotrophs. New Phytologist. 121:19-32.
Rawlings, N.D., F.R. Morton, C.Y. Kok, J. Kong, and A.J. Barrett. 2008. MEROPS: the peptidase database. Nucleic Acids Res. 36:D320-D325.
189
Redenbaugh, K., J.A.A. Fujii, and D. Slade. 1993. Hydrated coatings for synthetic seeds. 35-46 pp. Reichert, J.M. 2014. Antibodies to watch in 2014: Mid-year update. mAbs. 6:799-802. Reichert, J.M., C.J. Rosensweig, L.B. Faden, and M.C. Dewitz. 2005. Monoclonal antibody successes in
the clinic. Nat Biotech. 23:1073-1078. Rennels, M.B. 2000. The Rotavirus Vaccine Story: A Clinical Investigator's View. Pediatrics. 106:123-
125. Reuter, L.J., M.J. Bailey, J.J. Joensuu, and A. Ritala. 2014. Scale-up of hydrophobin-assisted
recombinant protein production in tobacco BY-2 suspension cells. Plant Biotechnol. J. 12:402-410.
Richter, A.K., E. Frossard, and I. Brunner. 2007. Polyphenols in the woody roots of Norway spruce and European beech reduce TTC. Tree Physiol. 27:155-160.
Richter, L.J., Y. Thanavala, C.J. Arntzen, and H.S. Mason. 2000. Production of hepatitis B surface antigen in transgenic plants for oral immunization. Nat Biotech. 18:1167-1171.
Riou-Khamlichi, C., M. Menges, J.M.S. Healy, and J.A.H. Murray. 2000. Sugar Control of the Plant Cell Cycle: Differential Regulation of Arabidopsis D-Type Cyclin Gene Expression. Molecular and Cellular Biology. 20:4513-4521.
Ritala, A., S.T. Häkkinen, and S. Schillberg. 2014. Molecular pharming in plants and plant cell cultures: a great future ahead? Pharmaceutical Bioprocessing. 2:223-226.
Rivas, J.D.L., J.J. Lozano, and A.R. Ortiz. 2002. Comparative Analysis of Chloroplast Genomes: Functional Annotation, Genome-Based Phylogeny, and Deduced Evolutionary Patterns. Genome Research. 12:567-583.
Rodrıguez-Monroy, M., and E. Galindo. 1999. Broth rheology, growth and metabolite production of Beta vulgaris suspension culture: a comparative study between cultures grown in shake flasks and in a stirred tank. Enzyme and Microbial Technology. 24:687-693.
Roels, S., C. Noceda, M. Escalona, J. Sandoval, M.J. Canal, R. Rodriguez, and P. Debergh. 2006. The effect of headspace renewal in a Temporary Immersion Bioreactor on plantain (Musa AAB) shoot proliferation and quality. Plant Cell Tissue Organ Cult. 84:155-163.
Rogers, G.L., A.M. Bryant, and L.M. McLeay. 1979. Silage and dairy cow production. New Zealand Journal of Agricultural Research. 22:533-541.
Roh, K.S., and B.Y. Choi. 2004. Sucrose regulates growth and activation of rubisco in tobacco leaves in vitro. Biotechnology and Bioprocess Engineering. 9:229-235.
Roitsch, T., and M.-C. González. 2004. Function and regulation of plant invertases: sweet sensations. Trends Plant Sci. 9:606-613.
Rojas-Martinez, L., R.G. Visser, and G.-J. de Klerk. 2010. The hyperhydricity syndrome: waterlogging of plant tissues as a major cause. Propag. Ornam. Plants. 10:169-175.
Ross, M.K., T.A. Thorpe, and J.W. Costerton. 1973. Ultrastructural Aspects of Shoot Initiation in Tobacco Callus Cultures. American Journal of Botany. 60:788-795.
Ruf, M., and I. Brunner. 2003. Vitality of tree fine roots: reevaluation of the tetrazolium test. Tree Physiol. 23:257-263.
Ruf, S., M. Hermann, I.J. Berger, H. Carrer, and R. Bock. 2001. Stable genetic transformation of tomato plastids and expression of a foreign protein in fruit. Nat Biotech. 19:870-875.
Ruf, S., D. Karcher, and R. Bock. 2007. Determining the transgene containment level provided by chloroplast transformation. Proceedings of the National Academy of Sciences. 104:6998-7002.
Ruhlman, T., R. Ahangari, A. Devine, M. Samsam, and H. Daniell. 2007. Expression of cholera toxin B-proinsulin fusion protein in lettuce and tobacco chloroplasts - oral administration protects against development of insulitis in non-obese diabetic mice. Plant Biotechnol J. 5:495-510.
Ruhlman, T., and H. Daniell. 2007. Plastid Pathways. In Applications of Plant Metabolic Engineering. R. Verpoorte, A.W. Alfermann, and T.S. Johnson, editors. Springer Netherlands. 79-108.
Ruhlman, T., D. Verma, N. Samson, and H. Daniell. 2010. The Role of Heterologous Chloroplast Sequence Elements in Transgene Integration and Expression. Plant Physiol. 152:2088-2104.
190
Russell, S.M., and F.Y. Liew. 1980. Cell cooperation in antibody responses to influenza virus. I. Priming of helper T cells by internal components of the virion. European Journal of Immunology. 10:791-796.
Rybicki, E.P. 2009. Plant-produced vaccines: promise and reality. Drug Discovery Today. 14:16-24. Rybicki, E.P. 2010. Plant-made vaccines for humans and animals. Plant Biotechnol. J. 8:620-637. Sabalza, M., P. Christou, and T. Capell. 2014. Recombinant plant-derived pharmaceutical proteins:
current technical and economic bottlenecks. Biotechnol. Lett.:1-13. Sabir, J., E. Schwarz, N. Ellison, J. Zhang, N.A. Baeshen, M. Mutwakil, R. Jansen, and T. Ruhlman.
2014. Evolutionary and biotechnology implications of plastid genome variation in the inverted-repeat-lacking clade of legumes. Plant Biotechnol. J. 12:743-754.
Saint-Jore-Dupas, C., L. Faye, and V. Gomord. 2007. From planta to pharma with glycosylation in the toolbox. Trends Biotechnol. 25:317-323.
Sajc, L., D. Grubisic, and G. Vunjak-Novakovic. 2000. Bioreactors for plant engineering: an outlook for further research. Biochemical Engineering Journal. 4:89-99.
Sánchez Pérez, J.A., E.M. Rodríguez Porcel, J.L. Casas López, J.M. Fernández Sevilla, and Y. Chisti. 2006. Shear rate in stirred tank and bubble column bioreactors. Chemical Engineering Journal. 124:1-5.
Sang, Y., R.J. Millwood, and C. Neal Stewart Jr. 2013. Gene use restriction technologies for transgenic plant bioconfinement. Plant Biotechnol. J. 11:649-658.
Santana-Buzzy, N., R. Rojas-Herrera, R.M. Galaz-Avalos, J.R. Ku-Cauich, J. Mijangos-Cortes, L.C. Gutierrez-Pacheco, A. Canto, F. Quiroz-Figueroa, and V.M. Loyola-Vargas. 2007. Advances in coffee tissue culture and its practical applications. In Vitro Cell. Dev. Biol.-Plant. 43:507-520.
Saski, C., S.-B. Lee, H. Daniell, T. Wood, J. Tomkins, H.-G. Kim, and R. Jansen. 2005. Complete Chloroplast Genome Sequence of Glycine max and Comparative Analyses with other Legume Genomes. Plant Mol.Biol. 59:309-322.
Savangikar, V. 2004. Role of low cost options in tissue culture. Low Costs Options for Tissue Culture Technology in Developing Countries:11-15.
Scheidt, G., A. Silva, Y. Oliveira, J. Costa, L.A. Biasi, and C.R. Soccol. 2011. In vitro growth of Melaleuca alternifolia Cheel in bioreactor of immersion by bubbles. Pak. J. Bot. 43:2937-2939.
Scheidt, G.N., A.H. Arakaki, J.S. Chimilovski, A.C.F. Portella, M.R. Spier, A.L. Woiciechowski, L.A. Biasi, and C.R. Soccol. 2009. Utilization of the bioreactor of immersion by bubbles at the micropropagation of Ananas comosus L. Merril. Brazilian Archives of Biology and Technology. 52:37-43.
Schillberg, S., N. Emans, and R. Fischer. 2002. Antibody molecular farming in plants and plant cells. Phytochemistry Reviews. 1:45-54.
Schillberg, S., N. Raven, R. Fischer, R.M. Twyman, and A. Schiermeyer. 2013. Molecular farming of pharmaceutical proteins using plant suspension cell and tissue cultures. Curr Pharm Des. 19:5531-5542.
Schnapp, S.R., and J.E. Preece. 1986. In vitro growth reduction of tomato and carnation microplants. Plant Cell Tissue Organ Cult. 6:3-8.
Schoberer, J., and R. Strasser. 2011. Sub-Compartmental Organization of Golgi-Resident N-Glycan Processing Enzymes in Plants. Molecular Plant. 4:220-228.
Schreiber, U., U. Schliwa, and W. Bilger. 1986. Continuous recording of photochemical and non-photochemical chlorophyll fluorescence quenching with a new type of modulation fluorometer. Photosynth Res. 10:51-62.
Schroeder, H.W., Jr., and L. Cavacini. 2010. Structure and function of immunoglobulins. The Journal of allergy and clinical immunology. 125:S41-52.
Scragg, A.H., E.J. Allan, and F. Leckie. 1988. Effect of shear on the viability of plant cell suspensions. Enzyme and Microbial Technology. 10:361-367.
191
Sethuraman, N., and T.A. Stadheim. 2006. Challenges in therapeutic glycoprotein production. Current Opinion in Biotechnology. 17:341-346.
Shaaltiel, Y., D. Bartfeld, S. Hashmueli, G. Baum, E. Brill-Almon, G. Galili, O. Dym, S.A. Boldin-Adamsky, I. Silman, J.L. Sussman, A.H. Futerman, and D. Aviezer. 2007. Production of glucocerebrosidase with terminal mannose glycans for enzyme replacement therapy of Gaucher's disease using a plant cell system. Plant Biotechnol J. 5:579-590.
Shann, F., and M.C. Steinhoff. 1999. Vaccines for children in rich and poor countries. Lancet. 354 Suppl 2:Sii7-11.
Sharma, A.K., and M.K. Sharma. 2009. Plants as bioreactors: Recent developments and emerging opportunities. Biotechnol. Adv. 27:811-832.
Sharma, M.K., N.K. Singh, D. Jani, R. Sisodia, M. Thungapathra, J.K. Gautam, L.S. Meena, Y. Singh, A. Ghosh, A. Tyagi, and A. Sharma. 2008. Expression of toxin co-regulated pilus subunit A (TCPA) of Vibrio cholerae and its immunogenic epitopes fused to cholera toxin B subunit in transgenic tomato (Solanum lycopersicum). Plant Cell Reports. 27:307-318.
Sharma, P., and R. Shanker Dubey. 2005. Modulation of nitrate reductase activity in rice seedlings under aluminium toxicity and water stress: role of osmolytes as enzyme protectant. J. Plant Physiol. 162:854-864.
Sharp, J.M., and P.M. Doran. 2001a. Characterization of monoclonal antibody fragments produced by plant cells. Biotechnol. Bioeng. 73:338-346.
Sharp, J.M., and P.M. Doran. 2001b. Strategies for Enhancing Monoclonal Antibody Accumulation in Plant Cell and Organ Cultures. Biotechnology Progress. 17:979-992.
Shaver, J.M., D.J. Oldenburg, and A.J. Bendich. 2006. Changes in chloroplast DNA during development in tobacco, Medicago truncatula, pea, and maize. Planta. 224:72-82.
Sheen, J. 1990. Metabolic repression of transcription in higher plants. The Plant Cell Online. 2:1027-1038.
Sheppard, A.E., M.A. Ayliffe, L. Blatch, A. Day, S.K. Delaney, N. Khairul-Fahmy, Y. Li, P. Madesis, A.J. Pryor, and J.N. Timmis. 2008. Transfer of plastid DNA to the nucleus is elevated during male gametogenesis in tobacco. Plant Physiol. 148:328-336.
Shimada, H., and M. Sugiura. 1991. Fine structural features of the chloroplast genome: comparison of the sequenced chloroplast genomes. Nucleic Acids Res. 19:983-995.
Shinozaki, K., M. Ohme, M. Tanaka, T. Wakasugi, N. Hayashida, T. Matsubayashi, N. Zaita, J. Chunwongse, J. Obokata, K. Yamaguchi-Shinozaki, C. Ohto, K. Torazawa, B.Y. Meng, M. Sugita, H. Deno, T. Kamogashira, K. Yamada, J. Kusuda, F. Takaiwa, A. Kato, N. Tohdoh, H. Shimada, and M. Sugiura. 1986. The complete nucleotide sequence of the tobacco chloroplast genome: its gene organization and expression. The EMBO Journal. 5:2043-2049.
Shirdel, M., A. Motallebi-Azar, S. Masiha, N. Mortazavi, M. Matloobi, and Y. Sharafi. 2011. Effects of inorganic nitrogen source and NH4
+ : NO3− ratio on proliferation of dog rose (Rosa canina). J
Med Plant Res. 5:4605-4609. Shuler, M., and F. Kargi. 2002. Bioprocess engineering: basic concepts. Prentice Hall international
series in the physical and chemical engineering sciences. Sikdar, S.R., G. Serino, S. Chaudhuri, and P. Maliga. 1998. Plastid transformation in Arabidopsis
thaliana. Plant Cell Reports. 18:20-24. Silhavy, D., and P. Maliga. 1998. Plastid promoter utilization in a rice embryogenic cell culture.
Current Genetics. 34:67-70. Singh, M., A. Boutanaev, P. Zucchi, and L. Bogorad. 2001. Gene elements that affect the longevity of
rbcL sequence-containing transcripts in Chlamydomonas reinhardtii chloroplasts. Proceedings of the National Academy of Sciences. 98:2289-2294.
Singh, S., M. Rai, P. Asthana, and L. Sahoo. 2010. Alginate-encapsulation of nodal segments for propagation, short-term conservation and germplasm exchange and distribution of Eclipta alba (L.). Acta Physiol. Plant. 32:607-610.
192
Singh, S.K., M.K. Rai, P. Asthana, S. Pandey, V.S. Jaiswal, and U. Jaiswal. 2009. Plant regeneration from alginate-encapsulated shoot tips of Spilanthes acmella (L.) Murr., a medicinally important and herbal pesticidal plant species. Acta Physiol. Plant. 31:649-653.
Sivakumar, G. 2006. Bioreactor technology: a novel industrial tool for high-tech production of bioactive molecules and biopharmaceuticals from plant roots. Biotechnol J. 1:1419-1427.
Soccol, C., G. Scheidt, and R. Mohan. 2008. Biorreator do tipo imersão por bolhas para as técnicas de micropropagação vegetal. Universidade Federal do Paraná. Patente,(DEPR. 01508000078).(in portuguese).
Sodoyer, R. 2004. Expression Systems for the Production of Recombinant Pharmaceuticals. BioDrugs. 18:51-62.
Solárová, J., and J. Pospíšilová. 1997. Effect of carbon dioxide enrichment during in vitro cultivation and acclimation to ex vitro conditions. Biol. Plant. 39:23-30.
Soria-Guerra, R.E., L. Moreno-Fierros, and S. Rosales-Mendoza. 2011. Two decades of plant-based candidate vaccines: a review of the chimeric protein approaches. Plant Cell Reports. 30:1367-1382.
Sowana, D.D., D.R.G. Williams, E.H. Dunlop, B.B. Dally, B.K. O’Neill, and D.F. Fletcher. 2001. Turbulent Shear Stress Effects on Plant Cell Suspension Cultures. Chemical Engineering Research and Design. 79:867-875.
Spira, S., M.A. Wainberg, H. Loemba, D. Turner, and B.G. Brenner. 2003. Impact of clade diversity on HIV-1 virulence, antiretroviral drug sensitivity and drug resistance. Journal of Antimicrobial Chemotherapy. 51:229-240.
Spök, A., S. Karner, A.J. Stein, and E. Rodríguez-Cerezo. 2008a. Plant molecular farming. Opportunities and challenges. JRC Scientific and Technical Reports.
Spök, A., R.M. Twyman, R. Fischer, J.K.C. Ma, and P.A.C. Sparrow. 2008b. Evolution of a regulatory framework for pharmaceuticals derived from genetically modified plants. Trends Biotechnol. 26:506-517.
Spörlein, B., M. Streubel, G. Dahlfeld, P. Westhoff, and H.U. Koop. 1991. PEG-mediated plastid transformation: a new system for transient gene expression assays in chloroplasts. Theor. Appl. Genet. 82:717-722.
Sreedhar, R., L. Venkatachalam, R. Thimmaraju, N. Bhagyalakshmi, M. Narayan, and G. Ravishankar. 2008. Direct organogenesis from leaf explants of Stevia rebaudiana and cultivation in bioreactor. Biol. Plant. 52:355-360.
Srinivasan, V., L. Pestchanker, S. Moser, T.J. Hirasuna, R.A. Taticek, and M.L. Shuler. 1995. Taxol production in bioreactors: Kinetics of biomass accumulation, nutrient uptake, and taxol production by cell suspensions of Taxus baccata. Biotechnol. Bioeng. 47:666-676.
Sriraman, R., M. Bardor, M. Sack, C. Vaquero, L. Faye, R. Fischer, R. Finnern, and P. Lerouge. 2004. Recombinant anti-hCG antibodies retained in the endoplasmic reticulum of transformed plants lack core-xylose and core-alpha(1,3)-fucose residues. Plant Biotechnol. J. 2:279-287.
Standardi, A., and E. Piccioni. 1998. Recent Perspectives on Synthetic Seed Technology Using Nonembryogenic In Vitro–Derived Explants. International Journal of Plant Sciences. 159:968-978.
Stanly, C., A. Bhatt, and C.L. Keng. 2010. A comparative study of Curcuma zedoaria and Zingiber zerumbet plantlet production using different micropropagation systems. Afr. J. Biotechnol. 9:4326-4333.
Staub, J.M., B. Garcia, J. Graves, P.T.J. Hajdukiewicz, P. Hunter, N. Nehra, V. Paradkar, M. Schlittler, J.A. Carroll, L. Spatola, D. Ward, G.N. Ye, and D.A. Russell. 2000. High-yield production of a human therapeutic protein in tobacco chloroplasts. Nat. Biotechnol. 18:333-338.
Staub, J.M., and P. Maliga. 1994. Translation of psbA mRNA is regulated by light via the 5′-untranslated region in tobacco plastids. Plant J. 6:547-553.
Stegemann, S., and R. Bock. 2009. Exchange of Genetic Material Between Cells in Plant Tissue Grafts. Science. 324:649-651.
193
Stegemann, S., S. Hartmann, S. Ruf, and R. Bock. 2003. High-frequency gene transfer from the chloroplast genome to the nucleus. Proceedings of the National Academy of Sciences. 100:8828-8833.
Steingroewer, J., T. Bley, V. Georgiev, I. Ivanov, F. Lenk, A. Marchev, and A. Pavlov. 2013. Bioprocessing of differentiated plant in vitro systems. Engineering in Life Sciences. 13:26-38.
Stern, D.B., and W. Gruissem. 1987. Control of plastid gene-expression - 3' inverted repeats act as messenger-RNA processing and stabilizing elements, but do not terminate transcription. Cell. 51:1145-1157.
Stern, D.B., D.C. Higgs, and J.J. Yang. 1997. Transcription and translation in chloroplasts. Trends Plant Sci. 2:308-315.
Steward, N., R. Martin, J.M. Engasser, and J.L. Goergen. 1999. Determination of growth and lysis kinetics in plant cell suspension cultures from the measurement of esterase release. Biotechnol. Bioeng. 66:114-121.
Stobbe, H., U. Schmitt, D. Eckstein, and D. Dujesiefken. 2002. Developmental stages and fine structure of surface callus formed after debarking of living lime trees (Tilia sp.). Ann Bot. 89:773-782.
Stoger, E., R. Fischer, M. Moloney, and J.K.-C. Ma. 2014. Plant Molecular Pharming for the Treatment of Chronic and Infectious Diseases. Annual Review of Plant Biology. 65:743-768.
Stoger, E., J.K.C. Ma, R. Fischer, and P. Christou. 2005. Sowing the seeds of success: pharmaceutical proteins from plants. Current Opinion in Biotechnology. 16:167-173.
Stoger, E., M. Sack, Y. Perrin, C. Vaquero, E. Torres, R. Twyman, P. Christou, and R. Fischer. 2002. Practical considerations for pharmaceutical antibody production in different crop systems. Molecular Breeding. 9:149-158.
Stoger, E., C. Vaquero, E. Torres, M. Sack, L. Nicholson, J. Drossard, S. Williams, D. Keen, Y. Perrin, P. Christou, and R. Fischer. 2000. Cereal crops as viable production and storage systems for pharmaceutical scFv antibodies. Plant Mol Biol. 42:583-590.
Strohl, W.R., and D.M. Knight. 2009. Discovery and development of biopharmaceuticals: current issues. Current Opinion in Biotechnology. 20:668-672.
Sugiura, M. 1992. The Chloroplast Genome. Plant Mol.Biol. 19:149-168. Svab, Z., P. Hajdukiewicz, and P. Maliga. 1990. Stable transformation of plastids in higher-plants.
Proc. Natl. Acad. Sci. U. S. A. 87:8526-8530. Svab, Z., and P. Maliga. 1993. High-frequency plastid transformation in tobacco by selection for a
chimeric aadA gene. Proceedings of the National Academy of Sciences. 90:913-917. Svab, Z., and P. Maliga. 2007. Exceptional transmission of plastids and mitochondria from the
transplastomic pollen parent and its impact on transgene containment. Proceedings of the National Academy of Sciences. 104:7003-7008.
Svensson, L., H. Sheshberadaran, S. Vene, E. Norrby, M. Grandien, and G. Wadell. 1987. Serum Antibody Responses to Individual Viral Polypeptides in Human Rotavirus Infections. Journal of General Virology. 68:643-651.
Tagliavini, M., J. Abadía, A. Rombolà, A. Abadía, C. Tsipouridis, and B. Marangoni. 2000. Agronomic means for the control of iron deficiency chlorosis in deciduous fruit trees. Journal of Plant Nutrition. 23:2007-2022.
Takayama, S., and M. Akita. 1994. The types of bioreactors used for shoots and embryos. Plant Cell, Tissue and Organ Culture. 39:147-156.
Takayama, S., and M. Akita. 2006. Bioengineering aspects of bioreactor application in plant propagation. In Plan Tissue Culture Engineering. Vol. 6. S.D. Gupta and Y. Ibaraki, editors. Springer Netherlands. 83-100.
Takeda, S., Y. Kaneko, H. Matsushima, Y. Yamada, and F. Sato. 1999. Cultured green cells of tobacco as a useful material for the study of chloroplast replication. Methods Cell Sci. 21:149-154.
194
Tan Nhut, D., T. Takamura, H. Watanabe, and M. Tanaka. 2001. Artificial light source using light-emitting diodes (LEDs) in the efficient micropropagation of Spathiphyllum plantlets. In II International Symposium on Biotechnology of Tropical and Subtropical Species 692. 137-142.
Tan, X.W., H. Ikeda, and M. Oda. 2000. The absorption, translocation, and assimilation of urea, nitrate or ammonium in tomato plants at different plant growth stages in hydroponic culture. Scientia Horticulturae. 84:275-283.
Tanaka, H. 1981. Technological problems in cultivation of plant cells at high density. Biotechnol. Bioeng. 23:1203-1218.
Tanaka, H. 1982. Oxygen transfer in broths of plant cells at high density. Biotechnol. Bioeng. 24:425-442.
Tavladoraki, P., E. Benvenuto, S. Trinca, D. De Martinis, A. Cattaneo, and P. Galeffi. 1993. Transgenic plants expressing a functional single-chain Fv antibody are specifically protected from virus attack. Nature. 366:469-472.
Teisson, C., and D. Alvard. 1995. A new concept of plant in vitro cultivation liquid medium: Temporary immersion. In Current Issues in Plant Molecular and Cellular Biology. Vol. 22. M. Terzi, R. Cela, and A. Falavigna, editors. Kluwer Academic Publ, Dordrecht. 105-110.
Teisson, C., and D. Alvard. 1999. In vitro production of potato microtubers in liquid medium using temporary immersion. Potato Research. 42:499-504.
Teng, W.L. 1999. Source, etiolation and orientation of explants affect in vitro regeneration of Venus fly-trap (Dionaea muscipula). Plant Cell Reports. 18:363-368.
Terrier, B., D. Courtois, N. Henault, A. Cuvier, M. Bastin, A. Aknin, J. Dubreuil, and V. Petiard. 2007. Two new disposable bioreactors for plant cell culture: The wave and undertow bioreactor and the slug bubble bioreactor. Biotechnol. Bioeng. 96:914-923.
Thiry, M., and D. Cingolani. 2002. Optimizing scale-up fermentation processes. Trends Biotechnol. 20:103-105.
Thomas, J.C., and F.R. Katterman. 1986. Cytokinin Activity Induced by Thidiazuron. Plant Physiol. 81:681-683.
Tichá, I., F. Čáp, D. Pacovská, P. Hofman, D. Haisel, V. Čapková, and C. Schäfer. 1998. Culture on sugar medium enhances photosynthetic capacity and high light resistance of plantlets grown in vitro. Physiologia Plantarum. 102:155-162.
Tiller, N., and R. Bock. 2014. The Translational Apparatus of Plastids and Its Role in Plant Development. Molecular Plant. 7:1105-1120.
Tillich, M., S. Beick, and C. Schmitz-Linneweber. 2010. Chloroplast RNA-binding proteins Repair and regulation of chloroplast transcripts. RNA Biol. 7:172-178.
Tissot, G., H. Canard, M. Nadai, A. Martone, J. Botterman, and M. Dubald. 2008. Translocation of aprotinin, a therapeutic protease inhibitor, into the thylakoid lumen of genetically engineered tobacco chloroplasts. Plant Biotechnol. J. 6:309-320.
Towbin, H., T. Staehelin, and J. Gordon. 1979. Electrophoretic transfer of proteins from polyacrylamide gels to nitrocellulose sheets: procedure and some applications. Proceedings of the National Academy of Sciences. 76:4350-4354.
Towill, L.E., and P. Mazur. 1975. Studies on the reduction of 2,3,5-triphenyltetrazolium chloride as a viability assay for plant tissue cultures. Canadian Journal of Botany. 53:1097-1102.
Towler, M., Y. Kim, B. Wyslouzil, M. Correll, and P. Weathers. 2006. Design, Development, And Applications Of Mist Bioreactors For Micropropagation And Hairy Root Culture. In Plan Tissue Culture Engineering. Vol. 6. S.D. Gupta and Y. Ibaraki, editors. Springer Netherlands. 119-134.
Tregoning, J., P. Maliga, G. Dougan, and P.J. Nixon. 2004. New advances in the production of edible plant vaccines: chloroplast expression of a tetanus vaccine antigen, TetC. Phytochemistry. 65:989-994.
195
Tregoning, J.S., P. Nixon, H. Kuroda, Z. Svab, S. Clare, F. Bowe, N. Fairweather, J. Ytterberg, K.J. van Wijk, G. Dougan, and P. Maliga. 2003. Expression of tetanus toxin Fragment C in tobacco chloroplasts. Nucleic Acids Res. 31:1174-1179.
Trejo-Tapia, G., A. Jiménez-Aparicio, L. Villarreal, and M. Rodríguez-Monroy. 2001. Broth rheology and morphological analysis of Solanum chrysotrichum cultivated in a stirred tank. Biotechnol. Lett. 23:1943-1946.
Tremblay, R., D. Wang, A.M. Jevnikar, and S. Ma. 2010. Tobacco, a highly efficient green bioreactor for production of therapeutic proteins. Biotechnol. Adv. 28:214-221.
Triguero, A., G. Cabrera, J.A. Cremata, C.T. Yuen, J. Wheeler, and N.I. Ramirez. 2005. Plant-derived mouse IgG monoclonal antibody fused to KDEL endoplasmic reticulum-retention signal is N-glycosylated homogeneously throughout the plant with mostly high-mannose-type N-glycans. Plant Biotechnol J. 3:449-457.
Tsai, C.-J., and J. Saunders. 1999. Evaluation of sole nitrogen sources for shoot and leaf disc cultures of sugarbeet. Plant Cell, Tissue and Organ Culture. 59:47-56.
Twyman, R.M., S. Schillberg, and R. Fischer. 2013. Optimizing the Yield of Recombinant Pharmaceutical Proteins in Plants. Current Pharmaceutical Design. 19:5486-5494.
Twyman, R.M., E. Stoger, S. Schillberg, P. Christou, and R. Fischer. 2003. Molecular farming in plants: host systems and expression technology. Trends Biotechnol. 21:570-578.
Uncu, A.O., S. Doganlar, and A. Frary. 2013. Biotechnology for Enhanced Nutritional Quality in Plants. Crit. Rev. Plant Sci. 32:321-343.
Vaidya, B., S. Mutalik, R. Joshi, S. Nene, and B. Kulkarni. 2009. Enhanced production of amidase from Rhodococcus erythropolis MTCC 1526 by medium optimisation using a statistical experimental design. J Ind Microbiol Biotechnol. 36:671-678.
Valdés, R., B. Reyes, T. Alvarez, J. Garcıa, J.A. Montero, A. Figueroa, L. Gómez, S. Padilla, D. Geada, M.C. Abrahantes, L. Dorta, D. Fernández, O. Mendoza, N. Ramirez, M. Rodriguez, M. Pujol, C. Borroto, and J. Brito. 2003. Hepatitis B surface antigen immunopurification using a plant-derived specific antibody produced in large scale. Biochemical and Biophysical Research Communications. 310:742-747.
Valkov, V.T., D. Gargano, C. Manna, G. Formisano, P.J. Dix, J.C. Gray, N. Scotti, and T. Cardi. 2011. High efficiency plastid transformation in potato and regulation of transgene expression in leaves and tubers by alternative 5' and 3' regulatory sequences. Transgenic Res. 20:137-151.
van den Dries, N., S. Giannì, A. Czerednik, F.A. Krens, and G.-J.M. de Klerk. 2013. Flooding of the apoplast is a key factor in the development of hyperhydricity. Journal of Experimental Botany.
van der Hoorn, R.A.L. 2008. Plant Proteases: From Phenotypes to Molecular Mechanisms. Annual Review of Plant Biology. 59:191-223.
van Dolleweerd, C.J., C.G. Kelly, D. Chargelegue, and J.K.-C. Ma. 2004. Peptide mapping of a novel discontinuous epitope of the major surface adhesin from Streptococcus mutans. Journal of Biological Chemistry. 279:22198-22203.
van Ree, R., M. Cabanes-Macheteau, J. Akkerdaas, J.P. Milazzo, C. Loutelier-Bourhis, C. Rayon, M. Villalba, S. Koppelman, R. Aalberse, R. Rodriguez, L. Faye, and P. Lerouge. 2000. Beta(1,2)-xylose and alpha(1,3)-fucose residues have a strong contribution in IgE binding to plant glycoallergens. The Journal of biological chemistry. 275:11451-11458.
Vasilev, N., U. Grömping, A. Lipperts, N. Raven, R. Fischer, and S. Schillberg. 2013. Optimization of BY-2 cell suspension culture medium for the production of a human antibody using a combination of fractional factorial designs and the response surface method. Plant Biotechnol. J. 11:867-874.
Vass, I., K. Cser, and O. Cheregi. 2007. Molecular Mechanisms of Light Stress of Photosynthesis. Annals of the New York Academy of Sciences. 1113:114-122.
196
Vdovitchenko, M.Y., and I.N. Kuzovkina. 2011. Artificial seed preparation as the efficient method for storage and production of healthy cultured roots of medicinal plants. Russ J Plant Physiol. 58:524-530.
Villani, M.E., B. Morgun, P. Brunetti, C. Marusic, R. Lombardi, I. Pisoni, C. Bacci, A. Desiderio, E. Benvenuto, and M. Donini. 2009. Plant pharming of a full-sized, tumour-targeting antibody using different expression strategies. Plant Biotechnol. J. 7:59-72.
Vlaev, S.D., and M. Fialova. 2003. Bubble Column Bioreactors: Comparison with Stirred Fermenters Based on Local Gas Hold-up Distribution. The Canadian Journal of Chemical Engineering. 81:535-542.
Vlahova, M., G. Stefanova, P. Petkov, A. Barbulova, D. Petkova, P. Kalushkov, and A. Atanassov. 2005. Genetic modification of Alfalfa (Medicago sativa L.) for quality improvement and production of novel compounds. Biotechnology & Biotechnological Equipment. 19:56-62.
Walch-Liu, P., G. Neumann, F. Bangerth, and C. Engels. 2000. Rapid effects of nitrogen form on leaf morphogenesis in tobacco. Journal of Experimental Botany. 51:227-237.
Walmsley, A.M., and C.J. Arntzen. 2003. Plant cell factories and mucosal vaccines. Current Opinion in Biotechnology. 14:145-150.
Wang, S.-J., and J.-J. Zhong. 2007. Chapter 6 - Bioreactor Engineering. In Bioprocessing for Value-Added Products from Renewable Resources. S.-T. Yang, editor. Elsevier, Amsterdam. 131-161.
Wang, Z.Y., X.D. Ye, J. Nagel, I. Potrykus, and G. Spangenberg. 2001. Expression of a sulphur-rich sunflower albumin gene in transgenic tall fescue (Festuca arundinacea Schreb.) plants. Plant Cell Reports. 20:213-219.
Ward, R.L., and M.M. McNeal. 2010. VP6: A Candidate Rotavirus Vaccine. Journal of Infectious Diseases. 202:S101-S107.
Watt, M.P. 2012. The status of temporary immersion system (TIS) technology for plant micropropagation. Afr J Biotechnol. 11:14025-14035.
Waugh, D.S. 2005. Making the most of affinity tags. Trends Biotechnol. 23:316-320. Weathers, P., C. Liu, M. Towler, and B. Wyslouzil. 2008. Mist reactors: principles, comparison of
various systems, and case studies. Electronic Journal of Integrative Biosciences. 3:29-37. Weathers, P.J., M.J. Towler, and J.F. Xu. 2010. Bench to batch: advances in plant cell culture for
producing useful products. Applied Microbiology and Biotechnology. 85:1339-1351. Webb, C., and B. Atkinson. 1992. The role of chemical engineering in biotechnology. The Chemical
Engineering Journal. 50:B9-B16. Weihe, A., K. Liere, and T. Börner. 2012. Transcription and Transcription Regulation in Chloroplasts
and Mitochondria of Higher Plants. In Organelle Genetics. C.E. Bullerwell, editor. Springer Berlin Heidelberg. 297-325.
Wheeler, T.R., P.Q. Craufurd, R.H. Ellis, J.R. Porter, and P.V. Vara Prasad. 2000. Temperature variability and the yield of annual crops. Agriculture, Ecosystems & Environment. 82:159-167.
Whitney, S.M., R.L. Houtz, and H. Alonso. 2011. Advancing Our Understanding and Capacity to Engineer Nature's CO2-Sequestering Enzyme, Rubisco. Plant Physiol. 155:27-35.
Wilken, L.R., and Z.L. Nikolov. 2012. Recovery and purification of plant-made recombinant proteins. Biotechnol. Adv. 30:419-433.
Will, G.M. 1966. Magnesium deficiency: the cause of spring needle-tip chlorosis in young pines on pumice soils. New Zealand Forest Service.
Wilson, S.A., and S.C. Roberts. 2012. Recent advances towards development and commercialization of plant cell culture processes for the synthesis of biomolecules. Plant Biotechnol. J. 10:249-268.
Wind, J., S. Smeekens, and J. Hanson. 2010. Sucrose: Metabolite and signaling molecule. Phytochemistry. 71:1610-1614.
Wise, R.R. 2006. The Diversity of Plastid Form and Function. In The Structure and Function of Plastids. Vol. 23. R. Wise and J.K. Hoober, editors. Springer Netherlands. 3-26.
197
Witcher, D., E. Hood, D. Peterson, M. Bailey, D. Bond, A. Kusnadi, R. Evangelista, Z. Nikolov, C. Wooge, R. Mehigh, W. Kappel, J. Register, and J. Howard. 1998. Commercial production of β-glucuronidase (GUS): a model system for the production of proteins in plants. Molecular Breeding. 4:301-312.
Wongsamuth, R., and P.M. Doran. 1997. Production of monoclonal antibodies by tobacco hairy roots. Biotechnol. Bioeng. 54:401-415.
Wood, D.W. 2014. New trends and affinity tag designs for recombinant protein purification. Curr Opin Struct Biol. 26:54-61.
Woodward, A.J., I.J. Bennett, and S. Pusswonge. 2006. The effect of nitrogen source and concentration, medium pH and buffering on in vitro shoot growth and rooting in Eucalyptus marginata. Scientia Horticulturae. 110:208-213.
Wright, A., and S.L. Morrison. 1997. Effect of glycosylation on antibody function: implications for genetic engineering. Trends Biotechnol. 15:26-32.
Wurbs, D., S. Ruf, and R. Bock. 2007. Contained metabolic engineering in tomatoes by expression of carotenoid biosynthesis genes from the plastid genome. Plant J. 49:276-288.
Xu, G., X. Fan, and A.J. Miller. 2012a. Plant Nitrogen Assimilation and Use Efficiency. Annual Review of Plant Biology. 63:153-182.
Xu, J., M.C. Dolan, G. Medrano, C.L. Cramer, and P.J. Weathers. 2012b. Green factory: Plants as bioproduction platforms for recombinant proteins. Biotechnol. Adv. 30:1171-1184.
Xu, J., X. Ge, and M.C. Dolan. 2011. Towards high-yield production of pharmaceutical proteins with plant cell suspension cultures. Biotechnol Adv. 29:278-299.
Yabuta, Y., M. Tamoi, K. Yamamoto, K. Tomizawa, A. Yokota, and S. Shigeoka. 2008. Molecular design of photosynthesis-elevated chloroplasts for mass accumulation of a foreign protein. Plant and Cell Physiology. 49:375-385.
Yan, H.B., C.X. Liang, and Y.R. Li. 2010. Improved growth and quality of Siraitia grosvenorii plantlets using a temporary immersion system. Plant Cell Tissue Organ Cult. 103:131-135.
Ye, G.N., P.T.J. Hajdukiewicz, D. Broyles, D. Rodriguez, C.W. Xu, N. Nehra, and J.M. Staub. 2001. Plastid-expressed 5-enolpyruvylshikimate-3-phosphate synthase genes provide high level glyphosate tolerance in tobacco. Plant J. 25:261-270.
Yoshikawa, T., and T. Furuya. 1983. Regeneration and in vitro flowering of plants derived from callus cultures of opium poppy (Papaver somniferum). Experientia. 39:1031-1033.
Zeeman, S.C., J. Kossmann, and A.M. Smith. 2010. Starch: Its Metabolism, Evolution, and Biotechnological Modification in Plants. Annual Review of Plant Biology. 61:209-234.
Zhang, R.Y., and W.D. Shen. 2012. Monoclonal Antibody Expression in Mammalian Cells. In Antibody Engineering. Vol. 907. P. Chames, editor. Humana Press. 341-358.
Zhang, Y.-h., J.-j. Zhong, and J.-t. Yu. 1996. Enhancement of ginseng saponin production in suspension cultures of Panax notoginseng: manipulation of medium sucrose. Journal of Biotechnology. 51:49-56.
Zhang, Z.-Y., and J.-J. Zhong. 2004. Scale-up of centrifugal impeller bioreactor for hyperproduction of ginseng saponin and polysaccharide by high-density cultivation of Panax notoginseng cells. Biotechnology Progress. 20:1076-1081.
Zhao, J. 2007. Nutraceuticals, nutritional therapy, phytonutrients, and phytotherapy for improvement of human health: a perspective on plant biotechnology application. Recent patents on biotechnology. 1:75-97.
Zhong, J.-J. 2002. Plant cell culture for production of paclitaxel and other taxanes. Journal of Bioscience and Bioengineering. 94:591-599.
Zhong, J.-J., K. Fujiyama, T. Seki, and T. Yoshida. 1994. A quantitative analysis of shear effects on cell suspension and cell culture of perilla frutescens in bioreactors. Biotechnol. Bioeng. 44:649-654.
198
Zhou, B., Y. Zhang, X. Wang, J. Dong, B. Wang, C. Han, J. Yu, and D. Li. 2010. Oral administration of plant-based rotavirus VP6 induces antigen-specific IgAs, IgGs and passive protection in mice. Vaccine. 28:6021-6027.
Zhou, F., J.A. Badillo-Corona, D. Karcher, N. Gonzalez-Rabade, K. Piepenburg, A.M.I. Borchers, A.P. Maloney, T.A. Kavanagh, J.C. Gray, and R. Bock. 2008. High-level expression of human immunodeficiency virus antigens from the tobacco and tomato plastid genomes. Plant Biotechnol. J. 6:897-913.
Zhou, F., D. Karcher, and R. Bock. 2007. Identification of a plastid intercistronic expression element (IEE) facilitating the expression of stable translatable monocistronic mRNAs from operons. Plant J. 52:961-972.
Zhu, L.H., X.Y. Li, and M. Welander. 2005. Optimisation of growing conditions for the apple rootstock M26 grown in RITA containers using temporary immersion principle. Plant Cell Tissue Organ Cult. 81:313-318.
Zimran, A., E. Brill-Almon, R. Chertkoff, M. Petakov, F. Blanco-Favela, E.T. Muñoz, S.E. Solorio-Meza, D. Amato, G. Duran, F. Giona, R. Heitner, H. Rosenbaum, P. Giraldo, A. Mehta, G. Park, M. Phillips, D. Elstein, G. Altarescu, M. Szleifer, S. Hashmueli, and D. Aviezer. 2011. Pivotal trial with plant cell–expressed recombinant glucocerebrosidase, taliglucerase alfa, a novel enzyme replacement therapy for Gaucher disease. 5767-5773 pp.
Ziv, M. 2000. Bioreactor technology for plant micropropagation. Horticultural Reviews. 24:1-30. Ziv, M. 2005. Simple bioreactors for mass propagation of plants. Plant Cell, Tissue and Organ Culture.
81:277-285. Zobayed, S.M.A., F. Afreen, and T. Kozai. 2000. Quality biomass program via photoautotrophic
micropropagation. Proceedings of the International Symposium on Methods and Markers for Quality Assurance in Micropropagation:377-386.
Zych, M., M. Furmanowa, A. Krajewska-Patan, A. Lowicka, M. Dreger, and S. Mendlewska. 2005. Micropropagation of Rhodiola Kirilowii plants using encapsulated axillary buds and callus. Acta Biologica Cracoviensia Series Botanica. 47:83-87.