Medical Biotechnology : Problems and Prospects in Bangladesh

Biotechnology is the knowledge and techniques of developing and using biological systems for deriving special products and services. The age-old technology took a new turn with the advent of recombinant DNA techniques, and boosted by the development of other molecular biological techniques, cell culture techniques and bioinformatics. Medical biotechnology is the major thrust area of biotechnology. It has brought revolutions in medicine – quick methods for diagnosing diseases, generation of new drugs and vaccines, completely novel approach of treatment are only a few to mention. The industrial and financial bulk of the industry mushroomed very rapidly in the last three decades, led by the USA and western advanced nations. Asian countries like China, India, South Korea, Taiwan and Singapore joined late, but advancing forward in a big way. In all the Asian countries governments supported the initiatives of the expert and entrepreneur community, and invested heavily in its development. Bangladesh has got great potential in developing biotechnology and reaping its fruits. However, lack of commitment and patriotism, and too much corruption and irresponsibility in political and bureaucratic establishment are the major hindrance to the development of biotechnology in Bangladesh.


Introduction
The central theme of biotechnology is using biological systems, an organism or any part of it, for derivation of special products or services to satisfy human need.A major part of the knowledge and discipline involves developing the organism or an appropriate part of it for the purpose, generating the product and processing.
The origin of the technology is often traced to making yogurt by using bacteria or fermenting beer by yeast.Before 1970s, the methods for getting a better organism were limited to searching among natural variants, selective breeding, hybridization, and induced mutation by chemical and physical agents.Despite some significant successes, this traditional biotechnology was not a well-known scientific discipline.
However, the nature of biotechnology was changed forever when Stanley Cohen and Herbert Boyer invented the recombinant DNA technology (also called molecular biotechnology, genetic engineering, gene cloning, gene splicing or gene transplantation) in 1973.DNA or Deoxyribonucleic Acid is at the root of all inherited characteristics of an organism.DNA contains the genesfunctional units of heredity each bearing a message of hereditary characteristic.The above scientists invented methods of recombining genes from different sources, thus producing "Genetically Engineered" ( G E) or "Genetically Modified" (GM) organisms with newer characteristics. 1 1.Identifying a gene (unit of inheritance) with desirable characteristic in one organism.
2. Isolate the gene 3. Introduce the gene to and express the characteristic in another organism [1][2][3][4] Before the advent of the above technology genetic materials of two organisms could be combined almost exclusively through sexual reproduction, which was possible only within a species and between closely related species or genera.Cross or hybridization, that is, sexual union crossing the species boundary, often resulted in sterile offspring.By hybridization technique it was impossible to combine genes, say of, rice and carrot, tomato and cow, etc.][6][7][8][9][10] An overview of the subdivisions and scope of biochemistry is illustrated in Figure 1.
What follows next is a very brief review of the fields of modern biotechnology in prevention, diagnosis and treatment of human diseases; followed by the global picture with particular emphasis to the Asian countries; and prospects, problems of its development and possible strategies of solution in Bangladesh.

Therapeutic proteins
Before the 1980s proteins were rarely used as drugs.
Exceptions were insulin and various vaccines.With the advent of genetic modification, however, human proteins have become available in huge quantities.
The first "bioengineered" drug, a recombinant form of human insulin, was approved by the U.S. Food and Drug Administration (FDA) in 1982. 11Until then, insulin was obtained from a limited supply of beef or pork pancreas tissue.By inserting the human gene for insulin into bacteria, scientists were able to achieve bacterial production of large quantities of the lifesaving protein.In the near future, patients with diabetes may be able to inhale insulin, eliminating the need for injections.Recombinant DNA products include, human serum albumin, human insulin, interferons, growth hormone, erythropoietin, etc. [12][13][14][15][16] Human proteins produced by recombinant DNA have several advantages.They are indistinguishable from their authentic human counterparts but are safer as they are less likely to be contaminated by infectious agents, and they can be produced in large quantities.A case in point is human growth hormone, which previously could only be obtained from human cadavers and carried the risk of Creutzfeld-Jakob disease (CJD). 17

Biotech vaccines
Biotechnology also plays an important role in preventing disease.Vaccines produced by recombinant DNA m e thods are generally safer than traditional vaccines because they contain isolated viral or bacterial proteins, as opposed to killed or weakened disease-causing agents.However, many citizens in developing nations do not have access to any vaccines, let alone ones derived from biotechnology.
In conventional vaccine production, the pathogen of interest is grown in the laboratory, collected and either killed or severely weakened before being injected into humans.The immune system then produces antibodies against the vaccine, protecting the body against future infection.If a fragment of the microbial DNA is used as an alternative vaccine, this will produce the antigenic protein directly in the body and may induce the immune system to produce antibodies.DNA v a ccines may be safer than conventional ones.They may also be easier t o manufacture and may be stable at room temperature.[20][21][22][23][24][25] The first recombinant vaccine, approved in 1986, was produced by slipping a gene fragment from the hepatitis B virus into yeast.The fragment was translated by the yeast's genetic machinery into an antigen, a protein found on the surface of the virus that stimulates the immune response.This avoided the need to extract the antigen from the serum of people infected with hepatitis B. [20][21] Because of their efficiency, safety, and relatively low cost, recombinant vaccines may have particular relevance for combating long-standing diseases of developing countries, including leishmaniasis (a tropical infection causing fever and lesions) and malaria.

Plants as bioreactor
Plants are being used as bioreactors for the biosynthesis of products with biotechnological interest.Plants have the ability to generate complex recombinant proteins with desired structures, maintaining biological functions.Transgenic plants can produce properly folded proteins at low costs and in large amount.Researchers have already demonstrated that recombinant proteins made in plants have similar biological activity as those produced in mammalian, yeast or bacterial cell culture.Plants also offer greater safety because they do not harbor mammalian pathogens or microbial toxins.[28][29][30][31][32][33][34][35] In addition to their use as bioreactors, plants can be used as potential delivery systems for oral vaccines.Edible biotherapeutics (edible vaccines), are very intriguing example.Currently, most vaccines require cold storage and professional administration through injection.Therefore, researchers are working on genetically engineered plants to deliver vaccines through food.The cost of plant-derived, orally administered hepatitis B vaccine is estimated to be one-sixth of the cost of current hepatitis B vaccines.Enough antigen to immunize all babies in the world each year could be grown on approximately 80 hectares of land. Transgenic animals By the early 1980s, scientists were able to insert DNA from humans into mice and other animals.
Because they now express human genes, "transgenic" animals can be studied as models for the development of diabetes, atherosclerosis, and Alzheimer's disease.They also can generate large quantities of potentially therapeutic human proteins.[47][48][49][50][51][52][53][54][55] Gene therapy Unlike conventional treatments, which attempt to deal with the consequences of a defect, gene therapy aims to correct the defect itself.In order to function, the therapeutic gene must reach the nucleus of the target cell.Various vectors have been used to achieve this, of which viruses were the first to be investigated.These have a natural ability to enter a cell and become active.
Current gene therapy systems suffer from the inherent difficulties of effective pharmaceutical processing and development, and the chance of reversion of an engineered mutant to the wild type.7] To address this issue, nanotechnological tools in human gene therapy have been tested and nanoparticle-based nonviral vectors (usully in size) in transportation of plasmid DNA d e scribed.[60] Whatever the vector, there are two methods by which gene therapy can be carried out: 1. in vivo gene therapy, in which the vector is injected into the body and has to find its way to the target tissue 2. ex vivo in which a sample of tissue is taken from the patient, treated with the vector and then replaced. 61[63][64][65][66][67][68][69] The use of viruses to deliver genes has shown risks to human health, making trials with these viruses controversial.Another method involves the use of liposomes, hollow membranous spheres which encapsulate the gene.Liposomes fuse with the cell membrane, releasing their gene into the cytoplasm. 66,69e convergence of nanotechnology with biotechnology will allow for safer gene delivery methods that are not based on viruses.Chemically synthesized nanoparticles that carry genes or therapeutics specifically to diseased cells are currently being tested in animals. 69

Antisense technology
In 1978, Paul Zamecnik of Harvard University demonstrated that the DNA to protein mechanism could be interrupted by the use of small synthetic stretches of DNA called oligonucleotides.He used an oligonucleotide with a sequence complementary to an mRNA molecule needed by a particular virus to reproduce itself.The oligonucleotide bound to the mRNA and stopped it moving onto the ribosome for translation.Early work is in progress to develop antisense technology as specific DNA drugs against cancer, viral infection and Crohn's disease (an inflammatory condition of the bowel).  Polyse chain reaction (PCR) Biotechnology also has dramatically improved diagnostic capabilities.The polymerase chain reaction, a method for amplifying tiny bits of DNA first described in the mid-1980s, a single segment of gene could be identified, copied, and tested within hours.It has been crucial to the development of blood tests that can quickly determine exposure to the human immunodeficiency virus (HIV), for example.Genetic testing currently is available for many rare disorders, such as hemophilia, which is caused by a mutation in a single gene.][94][95][96][97][98]

Development of human stem cells
Stem cells are the early-stage cells in an organism that have been shown to give rise to different kinds of tissues.They have successfully replaced or repaired damaged tissue in animal models, and they hold great promise for treating human diseases such as Alzheimer's and diabetes.Although the vast majority of people agree that cloning to produce humans (reproductive cloning) is unacceptable, therapeutic cloning, in which the cloning process is used only to harvest stem cells, is hotly debated.[101][102][103][104][105][106][107]

Monoclonal antibodies
The development of monoclonal antibodies in 1975 led to a similar medical revolution.Cesar Milstein and George Kohler won the Nobel Prize in 1984 for inventing a technique that produced the first monoclonal antibodies.The body normally produces a wide range of antibodies-immune system proteins-that root out microorganisms and other foreign invaders.By fusing antibody-producing cells with myeloma cells, scientists were able to generate antibodies that would, like "magic bullets," hone in on specific targets including unique markers, called antigens, on the surfaces of inflammatory cells.
Soon after their invention in 1970's the monoclonal antibodies (mAbs) earned the reputation of 'magic bullet,' in particular against tumor specific antigens and infectious diseases. 108The molecular biological techniques augmented both its accuracy and versatility. 109[115][116]

Bioinformatics
With the help of bioinformaticspowerful computer programs capable of analyzing billions of bits of genomic sequence datascientists are cracking the genetic codes to use the information for achieving various medical goals.For example by analyzing the codes of bacteria and discovering "weak spots" vulnerable to attack by compounds identified via high-throughput screening.[119][120][121][122][123][124][125][126][127][128]

Genomics and sequencing of human genome
The sequencing of the human genome, completed just three years ago, also has given scientists an incredibly rich "parts list" with which to better understand why and how disease happens.In the foreseeable future not only will every human gene will be identified, but the factors controlling their expression will also be known.This knowledge will unlock new targets for diagnosis, treatment and prevention of disease.[131][132][133][134][135][136][137] Proteomics Proteomics is about analyzing the complete set of expressed proteins in a given cell, 138 the path was open to understand emergent properties that result from the complex interactions of metabolic and regulatory networks.

Microarray technology
The automation of biochemical binding assays in small chips called microarrays enables scientists to screen thousands of chemical compounds for their effectiveness against disease-causing proteins in a very short time.This high-throughput screening, as it is called, would not have been possible without years of serious investment in basic biotechnology research.
A microarray is a two-dimensional arrangement of specific biological probes (e.g., DNA or protein molecules) deposited in an addressable fashion on a glass slide or other substrates (e.g., polymer-coated glass, plastics, nitrocellulose).The size of the glass slide is usually one by three inches, with thousands of isolated biological probes ranging from 50 to 300µm in diameter arrayed on the surface.Deoxyribonucleic acid (DNA), protein, [158][159][160] cell [161][162][163] and tissue microarrays [164][165] also called biochip microarrays, have helped understanding gene and protein functions.[168][169] Computer aided drug design Computer aided drug design is the use of omputational techniques to find out the characteristics of an appropriate drug molecule.Often a single molecule, for example a protein from a pathogen creates the whole range of disease features; or sometimes abnormal host molecules are the reasons behind the disease.In such cases the strategy to combat the disease is to introduce a new molecule that binds and inactivates the causative molecule.Traditionally almost blind search was performed among myriads of natural or synthetic substances.Computer aided drug design or rational drug design has cut the cost and time of drug search by several orders of magnitude.Today it is possible to select candidate drug molecules from huge available databases and check whether it can bind to the active site of the troublesome molecule using computational docking procedures. 117, Nano-bechnology Nano-biotechnology or nanomedicine is another rapidly moving field.Nanosensors are being developed from particles that are about 50,000 times smaller than the diameter of human hair to detect protein and gene expression in individual cells in the body, thus allowing the assessment of the health of cells at early stages of disease.Scientists are developing a wide variety of nanoparticles and nanodevices, scarcely a millionth of an inch in diameter, to improve detection of cancer, boost immune responses, repair damaged tissue, and thwart atherosclerosis.
[207][208][209] Global picture of biotechnology with emphasis to the Asian countries In all Asian countries, the governments are the ones driving biotech research.Private industry's role, in comparison, is miniscule.This is mainly because biotech research requires large investments in infrastructure and has a high cash-burn rate, while the returns in the initial years are quite low.[224] China forayed into biotech with a focus on plant genomics and transgenic technology.It was the only country from Asia that participated in the human genome project and is now shoring up its genome sequencing capability to facilitate the sequencing of microbial genomes. The government of India has established the Department of Biotechnology under the Ministry of Science and Technology, with huge budget to boost the advancement of biotechnology.The Government of India also took collaborative programs with UNESCO to establish the Regional Centre for research, training and education in biotechnology under the auspices of UNESCO.India is already being globally recognized as a manufacturer of economical, high-quality bulk drugs and formulations. In India the biotech industry has been growing at a double-digit rate over the last five years.The industry size stood at $4 billion for financial year 2010-11.Indian biopharmaceutical industry constitutes 60% of the biotech industry and grew at 21% to reach $2.3 billion in 2010-11.Vaccines, insulin, erythropoietin and monoclonal antibodies have been the mainstay of the biopharmaceuticals segment. 216iwan's medical bio-technology industry began in 1984 with government funding qualified laboratories to run recombinant DNA technology experiments.2] Singapore, too, has identified four key areas for structural improvement and better links between researchers and industry.[224] Applications in medical biotechnology are the more lucrative option for Asian countries, but this has high entry barriers and investment needs.With Asia's emergence as a preferred manufacturing base for bulk drugs and pharmaceutical dosage forms, and clinical development; it would be a move up the value chain for these players to extend these capabilities in chemistry into biology.The potential is furthered by the biopharmaceutical industry's rich research pipeline and greater expected therapeutic efficacy of clinical candidates for current lifestyle diseases.
About $126 billion worth of branded drugs are to go off-patent in the next 5 years, (from June 2012).While innovation is essential for sustainable longterm success, generic markets and services sector offers robust growth prospects.Asian firms can be expected to gain a strong foothold in the world generics markets given their strong chemistry and reverse engineering skills.

Challenges for Bangladesh
Biotechnology in general and Medical Biotechnology in particular is definitely a very prospective area of development for developing countries like Bangladesh, as the example of India shows.In Bangladesh although some biotechno-logical work and industrial initiatives in the traditional sense of the term has been taken, the field of modern medical biotechnology is still untouched.Only a few successful attempts has only been taken by international institutions in Bangladesh as ICDDRB.
The national institutions are yet to prove their capabilities and potentials.
A summary analysis of the situation in Bangladesh is given in the form of SWOT analysis below.

Concluding remarks
Biotechnology has the potential to provide more and healthier foods, reduce dependence on fossil fuels, offers more effective cures, diagnosis and prevention of diseases.It could be a shining path for industrial and economic development through generation of products and services both for domestic consumption and export.
The weaknesses on part of Bangladesh as noted above are addressable.However, the government must be the supporter and major investor in this effort, as the initial phase of development involves good amount of investment which would give only a delayed and diffused return, which the private sector is incapable to undertake.
The most optimistic feature of this fledgling technology and the industry is that: 1.It is not as capital intensive as other industries like chemical, automobile, electronic industries, etc.
2. In contrast it is more knowledge intensive, where intelligent people in a country like Bangladesh have got a fair advantage.
3. Small modular ventures could be taken by many entrepreneurs at a time, who may later form conglomerates at an appropriate time.
4. The know-how of the state of the art technology is still within reach of us.It has not advanced too far yet.Thus there is fair possibility that Bangladesh could get hold of it with an all out dash.

Fig 1 .
Fig 1.Major sub-divisions of Biotechnology and some of their products and services According to the global accounting firm Ernst & Young the total biotechnology industry revenues were about US$ 25 billion in 2000.Then it was predicted that it would be US$ 50 billion in 2010.But the reality exceeded the prediction.By 2005 the total revenue exceeded US$ 63 billion mark.Estimated global biotech industry revenues for publicly-held companies reached at $83.6 billion for 2011, up from $80.6 billion in 2010.Analysts at Morgan Stanley Research estimate that 7 of the best-selling drugs in the U.S. during 2010 were biotech drugs.Biotech drugs represent an estimated 10% of the total global prescription drugs market, and about 20% of the U.S. prescription market.210 Rich biodiversity Low cost of labor in research, development and manufacturing Fairly trained human resource Weakness Lack of commitment and patriotism, and too much corruption and irresponsibility on part of the political and bureaucratic establishment are the major weaknesses regarding development of the country in general, and biotechnology in particular.Emigration of the experts to rich countries Unawareness on part of entrepreneur community Disinterest in investing in research and development (R & D) by the national entrepreneurs Weak connection to the knowledge and information network Almost total absence of coordination between research and industry Poor coordination between national research institutes and resources Lack of venture capital Opportunities Fairly large local market Big export potential Scopes for contract research Threats Heavy investments by neighboring countries like India and China Anti-biotech propaganda, fueled by traditionalism and extreme 'environmentalism' Unfavorable intellectual property right (IPR) and trade policies imposed by the rich and technologically advanced countries or their representative agencies like World Bank and IMF.