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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5714_Библиотеки_им_академика_М_И_Перельмана.pdf
Medicine and Edible Vaccines
225
16. Reduced need for medical persons and sterile injection conditions
However, it has the following disadvantages:
1. Dosage of vaccines would be variable
2. Not convenient for infants
Edible vaccines offer promising future for providing therapeutic agents in order to make global
immunization program very successful, covering large contingent of people in developing and
underdeveloped countries.
QUESTIONS
1. What are edible vaccines?
2. What are major objectives of public health?
3. Give an account of basic sciences related to medicine.
4. Write a note on development of edible vaccines.
5. Write a note on challenges in production of edible vaccines.
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INTRODUCTION
Biotechnology is one of the world’s fastest growing and most rapidly changing technology,
involving biosciences that deal with genetically manipulating organisms. Biotechnology may
be considered as a great technical revolution in the last two decades. This branch of biosciences
has revolutionized the concept of production of drugs and therapeutics to save the mankind from
a lot of deadly diseases. The major impact of biotechnology is on the introduction of molecular
biology into medicine. It has led to powerful techniques known as genetic engineering, which
may be effectively used for synthesis of newer proteins as therapeutics using microorganisms.
Recent advancements in biotechnology have provided a new insight into many diseases and in
the developments of newer tools and techniques, which have brought revolutionary changes
in diagnosing, treating and preventing life-threatening diseases. Some of the important
biotechnological products that have revolutionized the field of medicine are as follows:
1. Therapeutics: Antibiotics, monoclonal antibodies (mAbs), insulin, growth hormones,
interferons, cytokines and monokines, colony-stimulating factors (CSFs), hormone-releasing
factor, immunosuppressive factor, clotting factor, clot-dissolving factor, neuroactive peptides,
anticoagulant factor, lipoproteins, vitamins and enzymes.
2. Vaccines: Hepatitis vaccine, herpes vaccine, rabies vaccine, polymyositis vaccine, influenza
vaccine, cholera vaccine, filariasis vaccine, AIDS vaccine and leishmaniasis vaccine.
3. Delivery system: Liposomes, biopolymers, plasmids and mAbs.
Broad Applications of
Pharmaceutical Biotechnology
15
CHAPTER
Introduction
Applications of Biotechnology in the
Production of Biomolecules
Applications of Biotechnology in the
Diagnosis of Diseases
Applications of Biotechnology in
Agriculture
Applications of Ultrasound to
Biotechnology
Testing of Pharmaceuticals
Questions
Textbook of Pharmaceutical Biotechnology
228
APPLICATIONS OF BIOTECHNOLOGY IN THE
PRODUCTION OF BIOMOLECULES
Production of Antibiotics
Antibiotics are generally defined as low molecular mass microbial secondary metabolites, which at
low concentration inhibit the growth of other microorganisms. Around 10,000 antibiotic substances
have been isolated and characterized so far. Several fungal genera are known to produce antibiotics.
Penicillin, the first antibiotic to be used medically, was extracted from Penicillium notatum.
Today, around 124 different antibiotics are available in the market, belonging to the different
classes, such as `-lactams, tetracyclines, aminoglycosides, macrolides, ansamycin, peptides and
glycopeptides.
Production of Vaccines
With the development of genetics, molecular biology and plant biotechnology in recent years,
production of vaccines (living vector vaccine, nucleic acid vaccine, etc.) has received special
impetus. In particular, the technology of transgenic plants to produce human or animal therapeutic
vaccines received increasing attention. Expressing vaccine candidates in vegetables and fruits open
up a new avenue for producing oral/edible vaccines. Transgenic plant vaccines are very promising
as they are low-cost products and are easy to store and convenient for immune inoculation. They can
be consumed directly without isolation and purification. Till date, many transgenic plant vaccines
have been produced.
Numerous vaccines are known today to protect mankind. Once inside the body, the vaccines, in
general, create a state that alarms the host in the same way, as in the case of a particular pathogen
attacking the body. Recent advances in immunology have led to the development of new and
promising strategies for vaccine production (Table 15.1).
New Generation of Vaccines
1. Hepatitis B vaccines: Numerous hepatitis B virus (HBV) vaccines are available in the market.
They can be broadly classified into hepatitis B surface antigen and recombinant HBV.
Table 15.1 Use of vaccines in different diseases and their strategic development
Disease Type of vaccine
Tuberculosis Attenuated
Cholera Inactivated
Plague Inactivated
Polio Inactivated attenuated
Yellow fever Inactivated exotoxin
Diphtheria/tetanus Inactivated exotoxin
Broad Applications of Pharmaceutical Biotechnology
229
2. Liposomal vaccines: HBsAg particle contains three peptides (small, middle and long peptide)
and lipids. The particle on encapsulation into liposomes serves as adjuvant carrier.
3. Contraceptive vaccines: The application of immunological approach for control of fertility
is a reality today. Birth control vaccines for human use have reached the stage of clinical trials
both in India and abroad. Today, vaccines against hormones such as luteinizing-hormone-
releasing hormone, follicle-stimulating hormone and human chorionic gonadotropin hormone
are in the process of development.
4. AIDS vaccines: Since HIV was identified as the causative agent of AIDS, enormous efforts
have been made to develop safe and effective vaccines.
5. Malaria vaccines: Malaria is a serious protozoan disease responsible for nearly one million
lives every year. A total of 85% of deaths occur in children below 5 years of age. Malaria
is caused by various species of the genus Plasmodium of which P. falciparum is the most
virulent and prevent. Current vaccine strategies are aimed at producing synthetic subunit
vaccines, consisting of epitomes that can be recognized by T cell and B cell.
6. DNA vaccines: These can serve as an alternative to immunization with purified protein and
are effective in generating antibody, helper and cytotoxic response and protective immunity.
7. Transgenic plants as edible immunogenic concept: A novel and practical approach for
development of vaccines could be through introduction of genes and encoding microbial
antigens in plants. An alternative approach to deliver the gene is by infecting the plant with
Clavibacter michiganensis, tobacco mosaic virus or by using gene gun.
Human Therapeutics from Recombinant DNA Technology
One of the greatest advantages of the recombinant DNA technology has been the production of
human therapeutics, such as hormones, growth factors and antibodies that are not only scarcely
available, but also are very costly for human use.
1. Recombinant hormones: Insulin (and its analogues), growth hormone, follicle-stimulating
hormone and salmon calcitonin
2. Blood products: Albumin, thrombolytics, fibrinolytics and clotting factors (factor VII, factor
IX, tissue plasminogen activator, recombinant hirudin)
3. Cytokines and growth factors: Interferons, interleukins and CSFs ( interferons _, ` and a),
erythropoietin, interleukin-2, granulocyte-macrophage CSF (GM-CSF) and granulocyte-CSF
(G-CSF)
4. Monoclonal antibodies and related products: Mouse, chimeric or humanized; whole
molecule or fragment; single chain or bispecific and conjugated (rituximab, trastuzumab,
infliximab and bevacizumab)
5. Recombinant vaccines: Recombinant protein or peptides, DNA plasmid and anti-idiotype,
hepatitis B surface antigen (HBsAg) vaccine and human papillomavirus (HPV) vaccine
6. Recombinant enzymes: Dornase alpha (Pulmozyme), alglucosidase alfa (Myozyme), alpha-
L-iduronidase (Aldurazyme), urate oxidase, etc.
7. Miscellaneous products: Bone morphogenic protein, conjugated antibody, pegylated
recombinant proteins and antagonists
Textbook of Pharmaceutical Biotechnology
230
Production in Lactic Acid
Lactic acid can be produced by either fermentation technology or chemical synthesis. Due to
environmental concern and the limited nature of petrochemical feedstock, the route of fermentation
technology has received considerable interest recently.
Lactic acid is widely used in food, cosmetics, pharmaceuticals and chemical industries as indicated
below.
1. Food preservative, flavour, pH regulator and mineral fortification
2. Cosmetic moisturizer, skin-lightening agent and antiacne agent
3. Pharmaceutical and chemical industries—parenteral/IV solution, dialysis solution, tableting
and surgical sutures
Plant Tissue Culture for Production of Plant Secondary Metabolites
Recent advances in the molecular biology, enzymology and fermentation technology of plant
cell cultures suggest that these systems may become a valuable source of important secondary
metabolites.
Plant tissue culture refers to growing and multiplication of cells, tissue and organs of plants
on defined solid or in liquid nutrient media under aseptic and controlled conditions. Some
important examples of secondary metabolite production from plant tissue culture are given in
Table 15.2.
Table 15.2 Recently produced bioactive secondary metabolites from plant tissue culture
Plant Active ingredient Type of culture
Allium sativum
Proteolytic enzymes Callus and tissue culture
Cassia acutifolia
Anthraquinone Suspension culture
Catharanthus roseus
Indole alkaloid Suspension culture
Cephaelis ipecacuanha
Cephaeline Callus culture
Cephaelis ipecacuanha
Emetine Callus culture
Cinchona ledgeriana
Quinoline alkaloids Globular cell suspension culture
Dioscorea deltoidea
Diosgenin Callus culture
Mentha arvensis
Terpenoid Shoot culture
Papaver somniferum
Sanguinarine Cell suspension culture
Panax ginseng
Ginsenoside Root culture
Podophyllum hexandrum
Podophyllotoxin Suspension culture
Salvia fruticosa
Rosmarinic acid Callus and suspension culture
Solanum elaeagnifolium
Solasodine Callus culture
Taxus species
Taxol Suspension culture
Withania somnifera
Withaferin Shoot culture
Broad Applications of Pharmaceutical Biotechnology
231
APPLICATIONS OF BIOTECHNOLOGY IN THE DIAGNOSIS OF DISEASES
The maximum benefits of biotechnology have been utilized in the production of potential drugs
( biotechnology-derived proteins and polypeptides). Currently, there are about 35 biotechnology-
derived therapeutics and vaccines approved by the USFDA alone for medicinal use. Additionally,
more than 500 drugs and vaccines are in the process of reaching the global market.
In medicine, modern biotechnology finds promising applications in the areas of drug production,
pharmacogenomics, gene therapy, genetic testing techniques in molecular biology and detection of
genetic diseases. Amniocentesis and chorionic villus sampling can be used for testing the developing
fetus for Down’s syndrome.
APPLICATIONS OF BIOTECHNOLOGY IN AGRICULTURE
The techniques of modern biotechnology may be used for development of a high-yield crop
variety with a new endogenic character. However, while increase in crop yield is the most obvious
application of modern biotechnology in agriculture, it is also the most difficult one. Current genetic
engineering techniques work best for effects that are controlled by a single gene. Many of the
genetic characteristics associated with yield (e.g. enhanced growth) are controlled by a large
number of genes, each of which has a minimal effect on the overall yield.
Reduced Vulnerability of Crops to Environmental Stresses
The biotechnological techniques may be successfully used for development of crops containing
genes that enable them to withstand biotic and abiotic stresses. The discovery of genes that enable
plants to overcome the limiting factors of drought and excessive salty soil has been made possible.
One of the latest developments is the identification of an antistress plant gene, At-DBF2, from a
tiny weed Arabidopsis thaliana. This is because it is very easy to grow, and its genetic code is well
mapped out. When this gene was inserted into tomato and tobacco cells, the cells were able to
withstand environmental stresses like drought, cold and heat, far more than ordinary cells.
Reduced Dependence on Fertilizers, Pesticides and Other Agrochemicals
The important application of modern biotechnology in the field of agriculture is on reducing
the dependence of farmers on agrochemicals. For example, Bacillus thuringiensis (Bt) is a soil
bacterium that produces a protein with insecticidal qualities. An insecticidal spray from this
bacterium is produced using fermentation technology. In this form, the Bt toxin occurs as an inactive
protoxin, which requires digestion by an insect to be effective. The crops may also be genetically
engineered to acquire tolerance to broad-spectrum herbicides. The lack of herbicides with broad-
spectrum activity and no crop injury is a consistent limitation in crop weed management. Multiple
applications of numerous herbicides are routinely used to control a wide range of weed species
detrimental to agronomic crops.
Textbook of Pharmaceutical Biotechnology
232
Production of Novel Substances in Crop Plants
The techniques of biotechnology are also being applied for novel uses in plant; for example, oilseed
can be genetically modified to produce fatty acids for detergents, substitute fuels and petrochemicals.
Potato, lettuce, safflower, tomato, rice, tobacco and other plants are genetically engineered to
produce insulin and certain vaccines. If future clinical trials prove successful, the advantages of
edible vaccines would be enormous, especially for developing countries. The transgenic plants may
be grown locally and with economic viability.
APPLICATIONS OF ULTRASOUND TO BIOTECHNOLOGY
The research related to application of ultrasound to biotechnology is of recent origin. Several
processes that take place in the presence of cells or enzymes are activated by high-intensity ultrasonic
waves, which can break the cells and denaturize the enzymes. Low-intensity ultrasonic waves are
capable of modifying cellular metabolism or improving mass transfer of reagents and products
through the boundary layer or cellular wall and membrane. In case of enzymes, the increase in the
mass transfer rate of reagents to the active site seems to be the most important factor. As compared
to native enzymes, immobilized enzymes are more resistant to thermal deactivation produced by
ultrasound waves.
TESTING OF PHARMACEUTICALS
By using biotechnological tools, the raw materials and their finished products of natural origin,
such as starch, gum, gelatin, talc, etc., can be tested for detection of various microorganisms.
Biotechnology has applications in evaluation of disinfectants and cleaning agents, for testing
biological activity of an antibiotic preparation and testing of endotoxin (bacterial endotoxin test).
The application and promise of biotechnology raised many ethical, economic, social and
environmental concerns across the globe. There has been resistance by certain groups of people for
the commercial use of genetically modified food or agricultural produce. Their main concerns are
related to adverse effects of this technology on health, nutrition and also on economic environment
prevailing in developing countries. If certain genuine concerns related to their misutilization are
taken care of, the science of biotechnology can offer very promising future to mankind.
QUESTIONS
1. What are the pharmaceutical applications of biotechnology?
2. Write about different scopes of biotechnology.
3. Give an account of applications of biotechnology in the production of biomolecules.
4. Give an account of applications of biotechnology in diagnosis of disease.
INTRODUCTION
Drug discovery is the process by which drugs are discovered and/or designed in the disciplines of
medicine, biotechnology and pharmacology. In the past, most of the drugs were discovered either
by identifying the active ingredient from medicinal plants or by serendipitous discovery. The quest
to discover healing drugs has always been influenced by prevailing social and cultural factor. A new
approach has been developed based on understanding how diseases and infections are controlled
at the molecular and physiological levels. The process of drug discovery involves identification
of candidates, synthesis, characterization, screening and assays for therapeutic efficacy. Once a
compound has exhibited its efficacy in these tests, the process of drug development begins prior
to clinical trials. Despite advances in technology and understanding of biological systems, drug
discovery is still a lengthy, difficult and expensive process with low rate of success.
In ancient times, accumulated knowledge and wisdom could only be passed on by word of
mouth from generation to generation. Ancient carvings and writing on the walls of caves held clues
to the early use of drugs. However, it was only the written accounts that led our ancestors to seek
out remedies for treating disease, such as those complied by the inhabitants of ancient civilizations
of India, Egypt, Mesopotamia (particularly Greece) and China.
The beginning of the 21st century has witnessed paradigm shift in the fields of biotechnology
and drug discovery. The research pertaining to discovery and the development of new drug entities
using computational methodology is undertaken in a big way. The success of modern drug research
depends on the rapid and universal publication of scientific results.
A drug may also interact elsewhere to produce an undesired effect. Plants contain a complex
and variable mixture of chemicals, and the risk of unwanted side effects occurring is always high.
Biotechnology in Drug Discovery
16
CHAPTER
Introduction
Current Trends in Modern Pharmaceutical
Analysis for Drug Discovery
Recent Pharmacokinetic Advances in Drug
Discovery and Development
Natural Product Drug Discovery
Questions
Textbook of Pharmaceutical Biotechnology
234
Biological testing
Lead generation
natural/screening/literature/leads
Chemical synthesis of new
compound
Preclinical trials
Figure 16.1 Drug discovery cycle.
The simplest way to minimize this is to isolate the compound that produces the desired response.
While this may be obvious today, it was not the reason behind the successful isolation of active
principles in the second decade of the 19th century (Figs. 16.1 and 16.2).
Figure 16.2 Structure-based drug design cycle.
High-resolution structure of ligand
Computational analysis and
rationalization of current SAR
Assaying and evaluation of
new compound
Synthesis of new chemical
series or compound
Design of new chemical
Improved lead
Lead compound selction
Determine target structure by
X-ray crystallography