comofarm/molecular farming action

Plants – our fi rst
line of defence?
Cost-friendly and easily scaled up, plants have come to the fore as a means of cultivating valuable
recombinant proteins. The CoMoFarm and Molecular Farming initiatives aim to capitalise on this
potential, opening up an avenue of research which could see the production of pharmaceuticals
capable of rapidly responding to emerging diseases – including pandemics and bioterrorist threats
COMOFARM/MOLECULAR FARMING ACTION
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The pick of the crop
Falling under the scope of the ‘Molecular Farming’ COST Action, the
CoMoFarm project is delivering exciting and promising contributions
to an area of research which is set to help Europe cement its position
as a leading player in the global molecular farming industry
COMOFARM IS A three-year FP7 project
focusing on the development of plantbased
production systems for the large-scale
manufacture of pharmaceutical and industrial
proteins. The project name is derived from the
phrase ‘contained molecular farming’, which
neatly summarises what the team has set out
to achieve. Essentially, the research group is
looking to develop plant-based systems that
can be used to produce large amounts of highquality
recombinant proteins in containment.
CoMoFarm is therefore focusing on ways to
improve product yield and consistency through
the development of standardised production
platforms based on whole plants, plant tissues
and plant cells, with automated monitoring
and maintenance systems to keep the plants
in peak condition. The project is coordinated
by Professor Stefan Schillberg from the
Fraunhofer Institute of Molecular Biology and
Applied Ecology (Fraunhofer IME) in Aachen,
Germany, and has a budget of €4.4 million,
2.8 million of which is funded by the European
Commission. The consortium includes 10
partner organisations from fi ve countries and
will come to a close in December this year.
A CATALYST FOR INNOVATION
The project was conceived because plants
have recently emerged as a highly promising
new paradigm for the production of valuable
recombinant proteins such as antibodies and
vaccines. Indeed, plants have many advantages
over current industry platforms which are
mostly based on bacteria, yeasts or mammalian
cells: they are inexpensive to cultivate; can be
grown on a large scale and scaled up rapidly; and
are safer than mammalian cells because they
do not support the replication of mammalian
viruses. Plants therefore appear ideal for
certain categories of pharmaceutical product,
such as those required on a massive scale (eg.
microbicides for topical application) and those
required to provide rapid responses to emerging
diseases (eg. vaccines against pandemics and
bioterrorist threats).
However, molecular farming in plants is still
at a relatively early stage of development
and lacks the years of optimisation that have
benefi ted microbial and mammalian systems.
These established platforms are handled using
standardised procedures and processes that are
approved by the regulators and guarantee quality
by design, allowing high-quality recombinant
proteins to be produced in a consistent manner.
More needs to be done to improve the quality
and consistency of plant-derived recombinant
proteins, so the CoMoFarm project aims to
42 INTERNATIONAL INNOVATION
COMOFARM/MOLECULAR FARMING ACTION
develop new technologies that standardise the
growth of plants and plant cells, helping them
to meet the standards of the current industry
favourites.
FROM ROOTS TO RESULTS
The project began with comparisons of four
different plant-based systems: whole plants
cultivated hydroponically, root cultures, moss
suspension cultures, and suspension cells. Each
system was represented by one or more species (eg.
tobacco, moss, rice and Arabidopsis suspension
cells), and each species/system combination was
used to produce up to three different proteins –
a recombinant monoclonal antibody, a secreted
version of the infl uenza hemagglutinin antigen
and a membrane-integrated version of the same
protein – to look at the impact of localisation on
product quality and consistency. The early aim
was to identify the best performers and eliminate
the others from the comparison, so that the focus
could be exclusively placed on strain and process
optimisation in the most promising platforms.
In parallel, the group has started to develop
new technologies that allow the automated
monitoring of plants, as well as plant tissues
and cells, so that growing conditions can be
monitored, adjusted and maintained to achieve
consistent plant growth and recombinant protein
production. This will be critical when considering
the validity of plant-based production platforms
under current regulations for the production
of pharmaceutical proteins according to good
manufacturing practice (GMP).
Progress during the project has been rapid. The
team has established all the different production
platforms and in most cases has succeeded in
the small-scale cultivation of lines, producing
one or more of the three target recombinant
proteins. This has provided the necessary
material to carry out an extensive comparative
characterisation to select the best performing
platforms for subsequent development,
resulting in the elimination of Arabidopsis and
rice suspension cells, as well as hydroponic
marshmallow plants and the retention of
tobacco plants, roots and suspension cells,
and moss suspension cultures. These platforms
have been used to investigate the cultivation
parameters (including nutritional factors,
physical conditions and molecular/genetic
properties) that provide an environment bestsuited
for optimal and consistent product yield
and quality. Currently, the CoMoFarm group is
testing combinations of optimised nutritional,
physical and molecular/genetic parameters
to see if they can achieve additive or even
synergistic improvements.

Success has also been achieved in the
development of several non-invasive monitoring
systems that can be used to continuously
monitor plant or plant cell/tissue health. These
systems either generate an alert in response
to poor health indications, or automatically
modify system parameters to compensate
suboptimal cultivation conditions. CoMoFarm
has developed early-stage concepts for
monitoring plants and plant cells by measuring
the chlorophyll content or the expression of a
fl uorescent marker protein. Meanwhile, systems
that monitor the health and productivity
of cultivated tobacco suspension cells and
roots by automatically measuring respiration
activity, scattered light and pH-dependent
fl uorescence, have also emerged as a result of
the project. A key task now involves integrating
these systems into optimised platforms to
achieve standardised, self-correcting growth
parameters, and the team has already began
work on this front.
THE SUM OF ITS PARTS
The CoMoFarm project is the fi rst to look at plantbased
production systems holistically, with a
view to optimising the entire production train
from cell to pure protein, focusing specifi cally on
pharmaceutical industry standards. The project
will involve many innovative elements including
in-process monitoring and the automation of
environmental parameter control to optimise
product yield, quality and homogeneity, novel
downstream processing technologies and
enhanced bioreactor and hydroponic designs
to keep plants and plant cells in peak health.
Ultimately, the results from the CoMoFarm
project will help to reduce the costs involved in
the production of pharmaceutical and industrial
proteins, and ensure that pharmaceuticals from
plants are produced to the highest possible
standards.
CoMoFarm is one of several EU projects that fall
within the scope of the COST Action ‘Molecular
Farming’. The COST framework promotes the ERA
and thus aims to integrate thematically-linked
research projects supported by national funds.
The ‘Molecular Farming’ Action is coordinated
by Professor Kirsi-Marja Oksman-Caldentey and
aims to establish a pan-European coordination
centre that promotes the exchange of technology
and knowhow between researchers working in the
fi eld of molecular farming. This is vitally important
because there are currently many competing
platforms based on plants, resulting in researchers
pulling in many different directions. Signifi cant
progress can be made by sharing expertise,
technologies and infrastructure to improve plant
biomass production, manufacturing, downstream
processing, purifi cation, product validation and
quality control, clinical trials, intellectual property
and regulatory issues. Importantly, the COST
Action has brought together key organisations
from developing countries, initially by inviting
them to participate in meetings and workshops.
This will result in full participation in research
projects and clinical networks. Ultimately,
this COST Action aims to build a sustainable
and competitive European molecular farming
community before the year is out.
INTELLIGENCE
COMOFARM/MOLECULAR FARMING ACTION
OBJECTIVES
The aims of the CoMoFarm project are to develop technologies that help to standardise the
growth and behaviour of plants, plant tissues and cells, allowing them to be used as highyielding
and consistent production systems for the large-scale production of high quality
pharmaceutical and industrial proteins.
The COST Action ‘Molecular Farming’ aims to build a sustainable European molecular plant
farming community with clear frameworks for regulatory, biosafety and intellectual property
issues.
PARTNERS
CoMoFarm:
Fraunhofer IME, Germany; Zürcher Hochschule, Switzerland; VTT Technical Research Centre
of Finland, Finland; RWTH Aachen BioVT, Germany; St George’s Hospital Medical School,
UK; Plant Research International, The Netherlands; Forschungszentrum Jülich, Germany;
greenovation, Germany; Dow AgroSciences, US/Germany; Kühner AG, Switzerland.
COST Action ‘Molecular Farming’:
More than 50 participating organisations from 23 signatory countries (Austria, Belgium, Bulgaria,
Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Iceland, Israel, Italy,
Lithuania, The Netherlands, Norway, Poland, Portugal, Slovenia, Spain, Sweden, Switzerland and
the UK), plus contributions from non-COST countries, including India and China.
FUNDING
CoMoFarm: FP7 KBBE; €4.4 million (EC contribution: €2.8 million)
COST Action ‘Molecular Farming’: FA0804; €350,000
CONTACT
Professor Stefan Schillberg
Project Coordinator, CoMoFarm
Plant Biotechnology
Fraunhofer IME
Forckenbeckstrasse 6
52074 Aachen
Germany
T +49 241 608 511 050
E stefan.schillberg@ime.fraunhofer.de
http://comofarm.org
Professor Kirsi-Marja Oksman-Caldentey
Coordinator, ‘Molecular Farming’ COST
Action
VTT Technical Research Centre of Finland
PO Box 1000
FI 02044 VTT (Espoo)
Finland
T +35 820 722 4459
E kirsi-marja.oksman@vtt.fi
http://molfarm.ueb.cas.cz
STEFAN SCHILLBERG graduated from the RWTH Technical University, Aachen, Germany in
1990 and was awarded a PhD in Molecular Biology from the same university in 1994. Since
then he has worked at the Fraunhofer IME in Aachen in diverse areas of plant biology and plant
biotechnology. He is currently Head of the Division of Molecular Biology at the Fraunhofer IME
in Aachen and Honorary Professor at the Justus-Liebig-University in Giessen.
KIRSI-MARJA OKSMAN-CALDENTEY defended her PhD in Pharmacy at the University of
Helsinki in 1988 and was appointed adjunct Professor in 1994. She is a well-recognised plant
biotechnologist and has worked both in academia and industry, building a large international
network around plant biotechnology. She has received numerous honorifi cs and nominations
in the fi eld of plant science. She is currently a Technology Manager at VTT Technical Research
Centre of Finland.
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