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Biotechnology and Society---Part 19
Economics of biopharmaceuticals
Once you hear the details of victory, it is hard to distinguish it from a defeat. - Jean-Paul Sartre (1905-1980), writer, philosopher
Currently more than 300
plant-made biopharmaceuticals are under various stages of discovery, development
and production at various academic and company sites around the world. Most of
the work goes on at academic or government institutions and has the potential to
spawn several new biotechnology companies for production of biopharmaceuticals.
Plants have one big advantage over mammalian cell systems in that plant viruses
are not pathogenic to humans unlike mammalian viruses.
We mentioned in the previous
article that biopharmaceuticals (which are not small organic drug molecules but
biological molecules such as proteins) that are used as therapeutics can be
manufactured using plants and animals instead of bacteria and mammalian cells in
an attempt to produce them inexpensively as also to mitigate the capacity crunch
in manufacturing plants.
Let us look at the methodology
and cost structure for such attempts. One has to remember that although these
transgenic technologies are quite facile, they have not been tested completely
by making human therapeutics in plants and animals and taking them to the
clinic, proving their equivalence and selling it in the marketplace after proper
approval by the government organisations in any country so far. But the day is
not far off before the drugs produced in plants and animals are marketed.
Technology: There are a
few techniques that are used to express a human therapeutic protein in plant
tissues. The human protein can be expressed in the whole plant, specific tissues
such as whole leaves, whole seeds or even specific regions of the leaves or
seeds. Basically, the process involves incorporating the desired foreign gene
into the genome of the plant to create a transgenic plant or introduce the gene
through external means into the plant and just transform that plant to make the
desired product.
The transformation to create a
transgenic plant can be effected in one of two ways. In one method, the foreign
gene is deposited on gold particles and bombarded onto the biological target
tissue by a technique called particle bombardment using a biolistic device
(biological ballistics). The gene is taken up by the tissue which can then be
grown into a plantlet and further into a plant in growth chambers and green
houses. A functional plant results from this operation and can be propagated for
planting in open fields. A schematic for this operation is shown below.
Genes to plant to seeds to
biopharmaceutical
In the operation mentioned
above the foreign protein is directed to be expressed in the seeds. The seeds
are harvested and the foreign protein can be purified.
In another method, the soil
pathogen, Agrobacterium tumifaciens, can be modified with the foreign gene and
the plant can be infected with the bacterium. The gene of interest gets
incorporated into the plant genome which can then be further propagated.
Several plants such as tobacco,
corn, rice, wheat, rapeseed, tomato, potato and mustard have been transformed
using these two techniques. However, it is not absolutely necessary that a
transgenic plant is created in order to make the therapeutic protein in the
plant. In order to meet objections that the transgenic plants have a potential
to spread into the environment some other techniques have been devised. These
involve asexual reproduction of plants, and developing male-sterile plants,
among other possibilities.
Tobacco: There have been
extensive research and development activities in making vaccines and other
therapeutic proteins in the tobacco plant, potato and banana. The vaccines
expressed in potato and banana can be consumed as “edible vaccines”. Tobacco
also fits the category of a non-food crop which is ideal to prevent
contamination of other food crops. There was a case of a transgenic corn
(expressing a vaccine) contaminating a soybean crop a couple of years ago.
Although there was no harm done it is better to use non-food crops to avoid any
such possibility of contamination.
Large Scale Biology Corporation
(Vacaville, California) is using a patented technique called GeneWare® which
involves growing a normal tobacco plant and then infecting it with a virus
called Tobacco Mosaic Virus containing the foreign gene of interest. The virus
has been tamed so that it does not spread or infect other plants. The foreign
protein concentrates in the leaves. The leaves can be harvested and processed to
isolate the therapeutic protein. Another company, CropTech Corporation, (which
recently went out of business) developed a technique called MeGA-PharM® whereby
the gene introduced enables the tobacco plant to develop normally and the
protein of interest is produced only upon causing an injury to the plant, in
this case harvesting the leaves.
In another technique involving
the tobacco plant, particle bombardment is used to introduce foreign genes into
leaf chloroplasts (the leaf tissues which contain the green pigment chlorophyll)
where the gene integrates into the genome and expresses the foreign protein.
There are about 100 chloroplasts per each cell in the leaf accounting to some
10,000 genome copies per cell. The gene is contained in the chloroplasts and not
the rest of the plant. This method enables biological containment by elimination
of the transmission of transgenes via the pollen or seeds.
Other systems: There are
some seeds which are rich in oil such as soybean, corn, rapeseed, peanut and
mustard. The oil is stored in such seeds as oil bodies with some structural
proteins known as oleosins. Human therapeutic protein genes have been fused with
the gene for oleosin and expressed as oil bodies. The oil bodies can then be
isolated and the protein of interest separated from oleosin.
Phytomedics, in Dayton, New
Jersey, and Photosynthetic Harvest Inc., in Willingboro, New Jersey, are two
companies which use patented technology called rhizosecretion in tobacco plants.
The roots of the plant continuously secrete recombinant proteins into a liquid
medium (hydroponic medium) thus simplifying the purification process. Biolex, in
Pittsboro, North Carolina, keeps its transgenic plants indoors. It uses a
fast-growing aquatic plant called Lemna (commonly known as duckweed) to produce
a variety of proteins including antibodies, interferon and human growth hormone.
The plant is not a crop plant but the foreign proteins can be expressed in the
biomass in large quantities.
Economics:
All these methods involve significant development costs. But once production
starts with the transgenic plants then the products can be manufactured quite
inexpensively. Let us look at a specific case of producing a therapeutic
antibody in the corn plant. One ear of corn contains 300-500 seeds and can
produce about 300 milligrams of an antibody at a cost of $ 20-30 per gram. The
economy of scale is very much evident if the transgenic corn is planted in
thousands of acres. The corresponding cost in a typical mammalian cell
production facility is estimated to be $ 200 per gram.
The timelines for production
are also quite advantageous. The turnaround time from germination to harvest is
roughly six months for corn. The crops can also be grown in northern and
southern hemispheres thereby enabling year-round production. Thus the plant
systems are quite viable for inexpensive production of therapeutic proteins.
It will be a while before
plant-produced therapeutics hit the market. Some issues like gene containment
need to be addressed so that society will accept the introduction of such
products knowing that there will not be any risks posed by the transgenic plants
to the environment.
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