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What is Red Biotech? It can be defined as biotechnology developed
and applied for medical purposes: diagnosis, prevention and treatment of various human
diseases. Medical application of biotechnology is reminiscent
of bloody color so it is called as red biotechnology. Biotechnology has been developed along with
human civilization. Since the middle of 1970s, genetic engineering
and monoclonal antibody production technology have lead the revolution of biotechnology
that can be readily used in the clinic.
Biotechnology can be defined as technology that processes or uses living organisms or
substances derived from living organisms for specific purposes.
The most primitive form of biotechnology has begun to utilize the natural environment in
the form of agriculture and livestock farming. For agriculture and livestock farming in early
civilization, selective breeding has been widely used to obtain the crops or livestocks
of desired properties. As you can appreciate from the fossils found
in Mexico remainings, wild corn had been dramatically improved to excellent crop over the centuries
by these methods. As fermentation process has been accidentally
discovered from food spoilage, fermentation has been widely used for artificial processing
of foods and various compounds. Fermentation techniques were performed at
the level of cottage industry until the Industrial Revolution.
Since then, fermentation technology has grown to the industrial scale to obtain various
fermentation products such as food additives and antibiotics.
As addressed before, development of genetic engineering techniques, monoclonal antibody
production and cell culture technology, have enabled us to produce biopharmaceuticals that
can overcome the limits of conventional small-molecule chemical drugs.
Biotechnology can be classified into three categories depending on the scope of application.
First, the traditional one is mainly applied for agriculture and livestock farming, or
pollution clearance, so-called bioremediation. This is referred as green biotechnology because
of the green color of crops. Second category is called as white biotechnology.
It involves production of food additives, medicinal compounds or bio-fuels and biodegradable
plastics by fermentation. Last one, which is the theme of this lecture,
is red biotechnology, as mentioned earlier developed for the diagnosis, prevention and
treatment of diseases.
Fermentation is the core of the classical biotechnology.
So Let's take a closer look. Fermentation is defined as a metabolic process
producing various organic compounds such as organic acids and alcohols by single cell
organisms such as yeast and bacteria. In narrow sense, fermentation is referred
to anaerobic metabolism of carbohydrates, mainly glucose.
Metabolic oxidation of organic compounds such as carbohydrates is called as respiration;
while fermentation processes take place in the absence of oxygen as anaerobic metabolism.
In general, cellular respiration converts glucose to carbon dioxide and water molecules
and generates large amounts of ATP (adenosine triphosphate).
However, in the absence of oxygen, glucose can be converted to lactate, and only a small
amount of ATP can be obtained through the fermentation.
Some metabolic products such as lactic acid, are essential for the growth and survival
of the microorganisms. Such metabolites are primary metabolites;
while secondary metabolites are referred to microbial metabolites that are not directly
involved in growth or survival of microorganisms. The best examples of secondary metabolites
are antibiotics, which are produced by numerous micro-organisms for suppression of neighboring
Industrial fermentation is widely used in five areas.
First, fermentation can be used for production of the microorganisms as biomass for food
source or yeast strain for baking industry. Second, the micro-organism-derived enzymes
can be obtained as the final products. Third, a variety of metabolites can be used
for dietary or medicinal purposes. And by the microbial fermentation, raw chemicals
can be transformed into the desired chemicals. Most of currently used antibiotics are now
produced by such biotransformation process. Finally, some microorganisms can be used to
clean up contaminated environment.
Traditionally, biopharmaceuticals are referred to recombinant proteins produced by genetic
engineering, cell culture, and hybridoma cell fusion techniques.
However, in recent days, gene therapy using nucleic acids, or therapy using stem cells
are also included as biopharmaceuticals in a broad sense.
Conventional small-molecule chemical drugs have relatively low specificity for the target
molecules, so the side effects are more frequent. Bioactive proteins and nucleic acids have
much higher specificity to the target molecules so the efficacy of the biopharmaceuticals
can be much higher while the side effects are drastically reduced.
Drug is the substance used for treatment or prevention of diseases or injury.
Sometimes, another term, medicine, is more specifically used for drug used for the treatment.
Natural products derived from plants or animals have been widely used as medicinal drugs for
centuries from the beginning of human civilization. Morphine was the first compound that has been
selectively isolated from natural herbal ingredients. In 1897, a chemist Hoffman synthesized aspirin,
a pure form of active ingredient included in the bark of the willow tree, which has
been known for its analgesic and anti-pyretic effect.
However, the modern pharmaceutical industry in true sense has only started from 1930s
after successful synthesis and mass production of sulfa antibiotics.
Unlike chemical drugs, biological materials were first used for prevention of fatal disease
at the end of the 18th century when Jenner used the vaccinia virus for protection of
fatal smallpox. The term, vaccination has been coined after
the first virus, vaccinia virus, used by Jenner.
Biological products similar to modern biopharmaceuticals have been first used for actual patients in
1920s, when Dr. Banting and Dr. Macleod isolated the insulin from the pancreas of pigs and
used for diabetic patients. In 1950s, many bioactive proteins such as
interferons or growth factors have been identified, but the amount of these bioactive proteins
are too low for practical uses. This limitation was overcome by monumental
development of genetic engineering in 1970s.
Genetic engineering, also known as recombinant DNA technology, is one of the core technology
for biopharmaceuticals. It involves in separation of DNA coding proteins
of interest and insertion of these DNA fragments into specific cells or organisms to amplify
the number of genes or produce the proteins of our interest.
These recombinant DNA technology can also be used for generation of transgenic organisms
by injecting foreign genes in living organisms to have a new trait.
For cloning specific gene, restriction enzymes and ligase enzymes are essential tool required
for proper editing of recombinant DNA.
Anothe core technology for biopharmaceuticals is hybridoma technique for production of monoclonal
antibodies. In general, one antigen have multiple antigenic
determinants, and each antigenic determinants can bind to different polyclonal antibodies
produced by multiple B cell clones. By selection of single B cell clone, we can
produce very specific antibody with high purity. These monoclonal antibodies can be produced
by fusion of single clone of B cells producing specific antibody with immortal cancer cells.
By doing so, the hybridoma cells can proliferate infinitely like original cancer cells and
produce monoclonal antibodies as well. To date, the majority of clinical approved
biopharmaceuticals are monoclonal antibodies. These antibodies can be produced in animals
mainly mice and rabbits; however, animal-derived antibodies can evoke unwanted immune responses
in human body. Such problems can be solved by production
of humanized version of monoclonal antibody.
Recombinant DNA technology and monoclonal antibody production technology would not be
possible if cell culture techniques have not been developed.
Cells of multicellular organisms such as human can be taken apart and grown artificially
in vitro, in other words, on the glass or in the flask.
However, these normal cells, so-called primary cells, can only be maintained for several
days or at best several weeks even in best conditions.
Then cells undergo rapid aging process after certain period of time after primary culture,
and this phenomena is called as biological clock.
Interestingly, this biological clock is not working properly in ever growing cells such
as stem cells and cancer cells.
Genetic engineering is the core technology of the Red Biotech and have huge impact on
biopharmaceuticals. First, genetic engineering technology has
solved the source availability problem especially for the bioactive proteins existing in very
low concentration in the body. By simple purification method, these bioactive
proteins could not be obtained in enough amount for practical uses.
Second, it can dramatically reduce risks of infection or contamination than can happen
during purification or refining step of bioactive proteins from the organisms.
Previously, hemophilic patients should get deficient coagulation factors by means of
concentrated plasma from hundreds of normal volunteers; however, these blood-derived products
were frequently contaminated by fatal viral heptitis or AIDS.
Production of recombinant coagulation factors by genetic engineering can eliminate the risk
of blood-borne contaminaton.
Thirdly, we can improve the efficacy of the recombinant proteins and at the same time
reduce the unwanted side effects by genetic manipulation of protein structure.
The best example is recombinant insulin used for lowering blood sugar in diabetic patients.
Insulin molecules aggregate with other insulin molecules once they are injected in subcutaneous
fat tissue. The aggregated insulin polymers then dissociate
slowly into soluble monomer and circulate the blood stream before arriving the target
tissues. And the insulin molecules are aggregated through
specific interaction of protein domains of insulin protein.
So genetic mofication of aggregation domain of insulin can change the degree of aggregation
and subsequently determine how fast the insulin can be dissolved into blood stream.
By this method, short-acting or long-acting insulins have been engineered and used for
Finally, genetically engineered transgenic animals are great tool to uncover the action
mechanism of drugs and validate the drug efficacy at the preclinical stage of drug development
Currently most of the biopharmaceutics used in clinics are protein-based drugs. Nucleic
acid-based gene therapy and cell therapy are only approved in limited countries.
Up to date, clinically available biopharmaceutical drugs include blood clotting factors, thrombolytic
agents, hormones, blood cell growth factors, vaccines, monoclonal antibodies, cytokines,
enzymes, and more.
The development process of bio-pharmaceuticals development is quite similar to that of the
conventional chemical drugs. In order to develop a new drug, it usually
takes about 10 years and more than 1 billion US dollars.
Most of this time and money are used to verify the efficacy of the drugs in actual patients
via clinical trials. Clinical trials are divided into three phases
according to the purposes and study protocol. Phase 1 clinical trial enrolls 20 to 100 healthy
volunteers to test the short-term side effects and determine the maximal tolerable dose for
In Phase 2 trial, about 100 patients and normal controls are tested for the relatively short-term
toxicity and efficacy of the drugs.
In the final step, phase 3 trial, large numbers of patients are test for long-term side effects
and efficacy. Only the drugs that survive the all three
steps are ready for clinical uses after approval by FDA.
Even though the drug development takes a lot of time and money, many multinational companies
are eager to develop new drugs. Then why?
It is because the drug industry is well-known high-risk high return market.
Drugs are sometimes called a blockbuster if the annual revenue is more than 1 billion
US dollars. Imagine that you own several such blockbuster
drugs, then your revenue is guaranteed for more than 10 years by patent, which will eventually
exceed the money you have to pay for drug development.
Biotechnology can be patented if the technology satisfies following four criteria: which are
novelty, non-obviousness, sufficiency of disclosure, and utility. Patent is possible if the ‘hand
of man’ has played an obvious part in developing the product. By this principle, many products
of nature have been successfully patented by enriching, purifying or modifying natural
products such as specific antibiotics, microorganisms, and proteins. However, as biotechnology makes
enormous innovation, there have been arising ethical and political issues on legal patenting,
such as human cloning and using human embryos for commercial purposes.
A summary of this of lecture is as follows:
First, biotechnology refers to technology processing life itself or a substance derived
from live organisms for specific purposes. Depending on the scope, it can be further
divided into green, white , and red biotechnology.
Second, red biotechnology is used for disease diagnosis, prevention and treatment by utilizing
genetic engineering , cell culture , monoclonal antibody production, and stem cell technology.
Third, the bio-pharmaceuticals are proteins or nucleic acids, and have higher specificity
against drug target compared to conventional small-molecule chemical drugs; therefore,
it has higher efficacy and less side effect.
Fourth, genetic engineering technology dramatically eliminated the risk of infection or contamination.
In addition, it can improve the efficacy or reduce side effects by changing the protein
structure of original proteins.
Fifth, the development of biopharmaceuticals is similar to that of conventional drugs,
which includes preclinical trials using laboratory animals and clinical trials.
Sixth, biotechnology can be patented if 1) they satisfies following four criteria: novelty,
non-obviousness, sufficiency of disclosure, and utility