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Molecular Farming
Author: Sandra Galeotti
Editors: Brenda Wilmoth Lerner and K. Lee Lerner
Date: Aug. 25, 2017
From: Biotechnology: In Context
Publisher: Gale, a Cengage Company
Series: In Context Series
Document Type: Topic overview
Length: 1,871 words
Content Level: (Level 5)
Lexile Measure: 1420L

Full Text:
Introduction
The use of genetically engineered microorganisms, plants, and animals to produce modified substances or molecules is known as
molecular farming. Also known as biofarming, molecular farming has the advantage of using renewable natural resources to produce
the desired substances. For farmers, molecular farming opens new doors for profitable opportunities by creating new market
segments. Molecular farming using either transgenic microorganisms or plants can provide huge quantities of recombinant proteins
for use in diagnosis reagent kits and therapeutic medications, such as antibodies, hormones, tumor markers, growth factors, and
other molecules needed in health care and life sciences research. Recombinant proteins can also be produced for other industrial
purposes.

Words to Know
Recombinant proteins
Proteins derived from genes inserted into the DNA of organisms that originally did not contain the genetic trait.
Codon
A sequence of three of the following four nucleotides: adenine, guanine, cytosine, and thymine, present in a strand of DNA or RNA.
Codons encode the genetic information to make a specific amino acid which will be incorporated into a protein chain or serve as a
termination signal. Codons are also known as triplets.
Monoclonal antibodies
Antibodies produced by a clone or genetically homogenous population of hybrid cells. Hybrid cells are cloned to establish cell lines
producing a specific antibody that is chemically and immunologically homogeneous.
Phytotherapeutics
Therapeutic substances naturally occurring in plants and used to make medications.
Historical Background and Scientific Foundations
For millennia, plants have been the main source of medications. Many modern phytotherapeutics were developed by studying herbs
already in use since ancient times. New biotechnologies allowed pharmaceutical companies to develop new synthetic and semi-
synthetic medications that are based on molecules naturally present in plants. Two such examples are vincristine and vinblastine, two
anticancer drugs structurally derived from the periwinkle plant Vinca rosea, which emulate the cytotoxic (cell-killing) effects of the
plant.
Before genetic engineering technologies were developed, hormones for human therapy, including insulin and estrogen, were
extracted from animal glands and purified by a complex and expensive process that, nevertheless, did not always yield the desired
degree of purity or molecular stability. The ability to produce human hormones by transferring the gene encoding a specific hormone
into bacteria has led to the mass production of recombinant hormones that do not cause allergies or other immunogenic reactions.

All organisms, from bacteria to mammals, share the same basic DNA structures named codons, which only differ in the sequence of
base pairs. Therefore, the transference of DNA from one organism into another became possible as soon as the required
technologies for genetic engineering were developed. Nature itself has always accomplished DNA recombination between species
through viral and bacterial infections. Viruses are considered by biologists to be a kind of universal genetic pollenizer because they
not only insert their own DNA in the host's genome, but also carry viral-host recombined DNA sequences from one host to the next.
Therefore, viruses disseminate recombinant genetic material throughout the entire food chain, from bacteria to plants, to animals, to
humans.

Most of the genetic material found in the structure of mammalian DNA is in fact viral and bacterial DNA. In the human genome, the
microbial genetic sequences represent up to 70 percent of the entire molecule. Recombinant technology used in molecular farming
has allowed humans to take advantage of this natural phenomenon in order to make many important human proteins in either
bacteria or fungi. Recombinant technology has also allowed scientists to recombine viral DNA to carry genes into targeted bacteria,
plant, or animal cells that are cultivated for a variety of purposes.

Molecular farming technologies, therefore, are based on the transfection of a gene encoding a molecule of interest in the DNA of
another organism that will be cultivated to produce that molecule in large quantities. As a result of advances in molecular biology, it
was possible to develop monoclonal antibodies, which are able to recognize specific proteins in cancer cells and elicit or enhance an
immune attack against tumors.

Molecular farming is fundamentally based on recombinant technologies. The first recombinant proteins, such as insulin and pituitary
hormones, were produced using bacteria. Transgenic bacteria are able to produce massive quantities of the desired molecule, which
is then completely separated from the bacterial medium and purified for therapeutic use. However, transgenic bacteria and fungi
require expensive equipment and facilities (with the specialized personnel required to run them), such as stainless steel tanks and
controlled temperatures, for mass production of molecules, whereas the cultivation of transgenic plants can be cost-effective and
much simpler.

Bacterial DNA cannot incorporate long gene sequences encoding large and complex proteins. This limitation led to experimentation
with animal cell cultures as production systems for recombinant proteins. Mammalian cells, including human cells, can be grown in a
culture medium and used to safely produce recombinant human proteins for therapeutic application. Nevertheless, animal or human
cell cultivation is also an extremely delicate process that requires bioreactors, additional immunogenicity testing, and pathogen
screening, thus costing many millions of dollars when produced in large scale for commercial use.

The use of plants as production biosystems, however, brings great advantages and cost reductions over unicellular molecular
farming, whether with bacterial or animal cell cultures. The production of hormones in transgenic plants such as soybeans, corn, or
tobacco leaves simplifies the extraction and purification process. It also has several other advantages such as: mass production (cost
reduction), absence of animal antibodies or immunogenic residues in the molecule (this means less expensive purification methods
and testing are necessary), as well as better quality control and consistency of the final product.

Plants began to be experimentally modified to express therapeutic molecules in the mid–1980s, and one of the first molecules
expressed in plants was insulin from corn. Presently, plants are used to produce serum albumin, recombinant growth hormones,
cytokines (interferon, interleukins), blood proteins, antibodies, vaccines, growth factors (epidermal growth factor inhibitors, vascular
growth factors,) and recombinant erythropoietin, among many other therapeutic molecules.

Impacts and Issues

As far as biosafety is concerned, plants are an ideal production system for recombinant biomolecules intended for human or animal
therapies. Furthermore, live animals and animal cell cultures are more costly and complex technologies than plant crops in terms of
safety, production time, storage, and distribution.

Another interesting aspect of molecular farming using plants instead of animals is that both bacteria and plants have been producing
and using hormones and enzymes for millions of years. Animals and humans did not invent their hormones. Nature's penchant for
frugality has simply conserved the genetic sequences encoding those molecules throughout species' evolution and differentiation.
Those conserved genetic traits, from bacteria to plants to animals (and humans) are known as evolutionarily conserved loci.
Therefore, molecules similar to insulin and steroidal hormones, for instance, were already being produced and used by bacteria and
plants long before humans evolved. Many naturally occurring hormones in plants have similar effects as those produced by human
glands; these are known as plant adaptogens.

The use of plants as production systems for molecular farming eliminates the risk of contamination with animal pathogens such as
viruses. Viruses that infect plants are usually not pathogenic to humans and other mammals. Transgenic plants can be grown on an
agricultural scale requiring only water, conventional fertilizers, and sunlight. They can also be easily transported and inexpensively
stored for later extraction of the molecule of interest, in contrast with unicellular molecular farming that generally requires
cryopreservation (freezing) of the produced molecules.

Molecular farming also provides advantages over microbial farming for bioremediation. Bioremediation refers to the use of
recombinant plants to remove toxins from polluted soils or water. Vast stretches of land are presently polluted with industrial chemical
residues (mostly petrochemicals) or with toxic heavy metals such as cadmium, mercury, or lead. Initially, some soil microorganisms
were the system of choice to remove pollutants through bioremediation, because they have a natural ability to degrade
petrochemicals through fermentation and to inactivate heavy metals by binding them to microbial proteins. However, there were
concerns about the potential problems that spraying soils with these microorganisms could create.

These concerns were left behind with the introduction of molecular farming with plants that bear the recombinant bacterial genes
responsible for the microbe's ability to remove pollutants from the soil. When engineered with these specific bacterial genes,
recombinant products that were produced by the plants were able to survive in polluted soils and remove the toxins as the bacteria
do. After the land is clean, the plants are harvested and burned under controlled conditions. Transgenic poplar trees were the first
plant species successfully transformed and used to detoxify soil.

The main potential environmental problem with the use of transgenic plants is the risk of transferring genetically modified traits to
other non-transgenic crops through pollination. Researchers have succeeded in developing restriction mechanisms to prevent such
gene flow, but some recombined plant species seem to be able to overcome these inactivating controls.

As molecular farming is intended to produce biologically active substances, including hormones and medications, in plants, there
have been strong concerns about inadvertent human exposure to these plants and the compounds they are engineered to make.
Accidental exposure could happen, for example, through contaminated harvesting equipment, or by interbreeding transgenic plants
with those intended for the food market.

Even more stringent confinement measures are imposed for field tests of pharmaceutical and industrial plants than for field tests of
conventional genetically engineered (GE) plants. These measures include larger isolation distances and fallow zones, and increased
inspections and oversight. During the growing season, care must be taken to achieve reproductive isolation from any sexually
compatible plants in order to prevent cross-pollination with cultivated or wild plants that are not part of the field test. Possible
environmental effects of molecular farming include potential impacts on threatened or endangered species, and toxicity of the GE
plant to non-target organisms. In cases involving introducing a new GE species, an environmental assessment is prepared
beforehand, followed by a waiting period designed to receive comments from the public.

The U.S. Department of Agriculture (USDA) issued strict, new regulations for molecular farming in plants in February 2006.
Pharmaceutical and industrial crops must be separated from other sexually compatible crops by a substantial distance. For example,
the isolation distance for open-pollinated corn is one mile, which is eight times further than is required for foundation seed production.
Other licensing requirements include: a 50-foot fallow zone surrounding the cultivation area; submission of seed handling protocols
for review; and employees and farmers must undergo an approved training program. Developers must have equipment and storage
dedicated to the pharmaceutical or industrial field trial. The same equipment and storage cannot be reused for crops beyond the field
test. Food or feed crops cannot be planted on the land that was used to produce pharmaceutical and industrial crops during the
previous season.

Books
Arora, Rajesh. Medicinal Plant Biotechnology. Wallingford, Oxfordshire, UK: CAB International, 2010.

Fischer, Rainer, and Stefan Schillberg. Molecular Farming: Plant-Made Pharmaceuticals and Technical Proteins. Weinheim,
Germany: Wiley-VCH, 2004.

Jaiwal, P. K. Plant Genetic Engineering, Volume 8: Metabolic Engineering and Molecular Farming. Delhi: Studium Press LLC, 2006.
Lim, Hwa A. Genetically Yours: Bioinforming, Biopharming, Biofarming. River Edge, NJ: World Scientific, 2002.

Web Sites
“Molecular Farming.” European Cooperation in Science and Technology (COST). http://molfarm.ueb.cas.cz/Molfarm.html (accessed
August 9, 2017).

“Molecular Farming for New Drugs and Vaccines.” European Molecular Biology Organization (EMBO) Reports, July 2005.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1369121/ (accessed August 9, 2017).

Full Text: COPYRIGHT 2012 Gale, Cengage Learning

Source Citation (MLA 8th Edition)
Galeotti, Sandra. "Molecular Farming." Biotechnology: In Context, edited by Brenda Wilmoth Lerner and K. Lee Lerner, Gale, 2012.
In Context Series. Gale In Context: Science,
https://link.gale.com/apps/doc/UFKSMP025165797/SCIC?u=made79693&sid=SCIC&xid=6face065. Accessed 18 Feb. 2020.
Gale Document Number: GALE|UFKSMP025165797