Friday, October 1, 2010


Part II

Priority and choice in the Biotech sector

Around the world, of all the sectors of biotechnology, health care is presently receiving highest attention for technology development and product use. The major product groups are r-DNA based therapeutic substances, vaccines, diagnostic devices and humanized monoclonal antibodies. Stem cell research is also progressing with rapt attention. Tissues specific deliveries through nano technology are other areas of considerable interest.

In the development of r-DNA products it is important to develop expertise in the cloning of certain cell types. Most of the presently used products deploy Eschricia coli, Saccharomyces cerevisae. , Pichia pastoris, Hansenula polymorpha and Chinese Hamster Ovary (CHO) cell lines as their workhorses. In a few cases, BHK and VERO cell lines have been used. Baculovirus mediated insect cell lines are also gaining acceptance. Indian industry has narrowed down its choice to E.coli, P.pastoris , and CHO cell line based products; only one company has preferred to choose insect cell lines. More than 60% of the modern biotech products, which are mainly highly glycosylated therapeutic proteins, are presently made in CHO cell lines. Therefore, Indian expertise in the handling and use of CHO cell lines must enlarge and increase.

Biotech operations are another important area where right choice of processes must be made. Since the volumes are small, the use of glass reactors or the SS reactors for cell multiplication can be alternate choice options. If CHO cell lines are the main workhorses, it is beneficial to look for disposable plastic bioreactors to cut down the cost of sterilization, which is sizable.

Chromatography is a down stream processing operation of choice where standardization is required to minimize the use of columns; rugged columns with efficient resin matrices must be used that can be resorted to cleaning in place (CIP). Membrane adsorption techniques can be coupled with multi-tier chromatography to enhance through puts. India is not yet an efficient producer neither for resin matrices nor for separating membranes.

Formulation development is another area where success would depend upon simplification and the use of simple, easily sterilizable substances. In all these areas, Indian development is expected to be significant in coming years.

Stem cell research has picked speed and products are on the horizon. Autologous transplants using in-vitro cell culturing are on the rise. One aspect of the activities comprises isolation and preservation of the embryonic stem cells. This work had made considerable progress with the hope that methods shall soon be in place to multiply them in the desired direction for differentiation to meet the tissue specific deficiency needs. Such manipulative generic procedures have not evolved yet. Therefore, embryonic stem cells preservation has slowed down. Another technology is under development; efforts are being made to develop the re-programming techniques to induce pluripotency in aged genomes to reverse the aged DNA in to their youthful forms. Such work requires advances in retro and non-retroviral means of over expression of certain oncogenes into engineered cell types. Non-retroviral means would be preferred as the retroviral means change the chromosomes considerably through the insertion of viral DNA, which is not preferred. Research in these directions is very expensive; success is not assured. Therefore, Indian focus of research in these areas may be diminutive.

Tissue target specific deliveries requiring use of biodegradable polymers and nano particles are other areas where high technologies can be developed and Indian industries can be set up.

In agriculture, production of transgenic plants has made considerable progress around the world. The application areas are based on nuclear integration of a wide range of transgenes. Therefore, the traits are expressed in both pollens and angiosperms. Transgenic DNA insertion only into the chloroplasts is being experimented upon to impart and preserve transgenic characters only in the maternal part of the plant. Commercial plants are not yet released. This technology, when matured and made to commercial use shall put to rest several environmental risk issues. Transgenic animals are yet at the developmental stage for application; some transgenic fishes containing multiple copies of growth hormone genes have been released, which have increased feed conversion ratio.

In Indian context, biotech seeds and planting materials hold great potential. The Bt-cotton story is revealing; extensive deployment of transgenic Bt –cotton has not only been responsible for increased production of better quality of cotton lint, the technology has also reduced the usage of chemical pesticides in the environment. The technology is deployed from multiple sources, resulting in severe competition and reduction in the selling price of GM seeds. In order to sustain Bt-technology over the years, multiple Bt-genes inserted plants need to be developed and deployed to delay the emergence of inset-resistance in the field. Bt-technology means insertion of the toxin producing genes of Bacillus thuringiensis, mostly known as Cry genes of the bacterium; Bt-Cotton contains Bt-Cry1Ac genes covalently inserted into the genome of the cotton plant.

The apparent success of Bt-cotton technology in India has not been able to promote usage of genetically modified planting materials for other crops. The main impediments are: a) Environmental safety issues, b) Human and animal food safety issues and c) the issue of dominance of private seed companies thereby transferring control of agriculture and especially food to them.

The environmental concerns hover around the threat of contaminating the closely related natural germplasms, cultivated or wild, by transgenic nucleotide sequences, spreading residual toxins secreted by insect-toxin-producing genetically modified (GM) plants, in to the soil, and resistance development in the target insects in situations where GM plants code for toxic proteins. Besides, some GM plants may carry antibiotic resistant genes; their free access to agriculture may hasten the development of pathogenic microbes in to antibiotic resistant substances. On food safety issues, different models of animal feeding trials have been designed and data generated.

All the above issues are always taken in to consideration by the regulatory authorities and decisions are made based on scientifically generated data on a precautionary principle. However, having regard to the limitations in the scientific tools as developed presently, certain issues cannot be fully resolved. Different countries have therefore taken different stand on GM plants. Fortunately, whichever countries used the technology in their soil, they stood to gain. Several countries have adapted to production of GM crops. Up to 2009, 25 countries all over the world had planted 134 million hectares to produce maize, cotton, soybean, canola, squash, papaya, tomato, potato, beet and alfalfa as major crops. All countries including USA, Canada, Mexico, South American countries, Australia, China and India have benefited from GM crops. In Europe, Spain, Portugal and certain East European countries like Czech Republic, Poland, Slovakia and Romania have adopted GM technology. Europe, Russia, Ukraine and Kazakhstan, Japan, Arabian countries and African countries (except South Africa) have not yet used this technology; their reluctance to this technology is not well understood.

The argument about creating dominance of private seed companies for GM crops/seeds can be addressed by conducting more research in public funded institutions. Concomitantly, a strong environment of competition has to be created by enabling multiple players to enter in to the market place. Multinational dominance can then be minimized and prices of GM plants/seeds can be rationalized. This has happened to a great extent in Indian Bt-Cotton technology application; there are several players in the market place, and as a result market forces have considerably rationalized the prices of GM-seeds of Bt-Cotton.

India has not yet created its strong presence in research in GM crops in its public funded institutions. If this is done, the benefits would accrue. GM plants have great possibilities of contributing to agricultural productivity, other inputs being same.

GM fishes are also other areas where the world community is strongly pursuing research. The feed conversion ratios are being improved by incorporating multiple copies of growth hormone genes into economically important fish. Such experiments can also be carried out in birds and animals. Indian developments or success stories in these areas are meager.

India must prioritize
Human health and agriculture are the two main sectors in modern biotechnology which are expected to impart considerable gains to the country.

Health of the people decides how the economy of a country shall be. Good community health determines the social development; it is the indicator of the earning power or the poverty- status of people. Medicines from modern biotechnology shall ensure prevention and recovery much quicker. But they must be available for use. The disease burden must therefore be addressed in the national context. Several neglected diseases of the poor including tuberculosis, malaria, diarrhea, trypanosomiasis, dengue, leishmaniasis and lymphatic filariasis are responsible for many man-day losses in productivity. HIV is also becoming a major threat. Indian biotech has to address these problems and come out with robust solutions. In other major areas that contribute to significant loss of man-days such as diabetes, cardiovascular diseases, cancer and mental health disorders, efforts have to be made to have access to current biotech drugs to treat these disorders. The innovation platform can be drawn up professionally on a national drawing board. The plan needs to be piloted by the government, which has to generously shell out the resources through a mechanism involving the industry, the specialists who would invent and discover, the money providers and the vocal public. Private money for basic research may be available after public institutional research starts bearing fruits.

With the rise of the growing middle class and with microeconomic growth percolating to the rural areas, there will be the creation of demand for the latest biotech drugs. It is anticipated that the basic production of many of these would not be possible locally due to strong protection of existing technologies and their non-availability to others even though there are compelling reasons. To meet the needs of the poor people in India is different from meeting those in the developed countries. Poor men in India run a much more handicapped race for survival than their counterparts in rich countries. To bring in equity to Indian poor people, government may have to step in and create an enabling environment. Provisions in the existing Indian Patent Law may be inadequate for instituting compulsory licensing authorization. Newer approaches for registration/authorization for the sale in India for the expensive imported products, required for masses in life-threatening situations may emerge in the country in public interest. The provisions of Essential Commodities Act of the country may become handy to tackle such situations.

One of the elements of success in the long term lies in the conduct of basic research. But India has to prioritize its need-based areas, where basic research has to be intensified. It would not be beneficial to pursue the same areas of basic research that the skilled scientists learn elsewhere, which has less relevance to Indian needs. The question is how some of the basic needs can be addressed through basic research and how can this be made attractive to the young scientists.

There is a great need to develop innovative processes for biogenerics and bio-similar products. These can be low pick fruits. A large number of these have become off patent and many others are going out of IPR. Innovations for developing biogenerics scarcely attract the best talent. This is because such work often does not lead to high-class publications. There is a need to develop strategies to attract young talented scientists in this area.

Mass production of multivalent vaccines and diagnostic agents at affordable prices shall enable the improvement of health of Indian children as well as the aged. This will make a great impact to the country. Products can also be exported. India has developed great skills in these areas. More can be done to meet the global needs of the poor.

Novel drug delivery and nano technology require relatively less investment. Industry can concentrate to develop products in these areas for diverse applications.

In all the above areas, innovative processes and products cannot generate extraordinary revenues. There shall be the presence of several companies to explore the opportunities and therefore severe competition will compel reduction of prices, thereby affecting profitability. Some successful companies shall make gain through these activities; however, the revenues shall not be able to generate enough surpluses to plough back for conducting basic research. There is no escape from entering into basic research if the aim is to develop jackpot products. Novel products can only generate enough surpluses, part of which can be ploughed back for more basic research.

In agriculture, basic research for developing highly productive plants and animals including fishes can be intensified in a planned manner so as to harvest the benefits over a period of time. Agricultural productivity increase is driven by scientific discoveries, innovation, new technology development and their adoption by farmers. Of the various discoveries in agriculture, development of GM plants and animals hold great promise Plants must be selected to develop national programs for productivity increase. Field crop improvement through rapid DNA sequencing followed by selection of better genomic traits, use of marker assisted breeding, deployment of double haploid breeding for crossing species and selected such techniques can be extensively used to improve productivity. Projects can be implemented on selected plants for improving the nutritional quality of cereals by enhancing levels of proteins, carbohydrates (where applicable), oil, anti-oxidants and vitamins. Oil bearing seeds need to be selected to convert them into GM plants that produce specific kinds of oils to meet human health and other needs. Basic research may be intensified for the identification and isolation of drought resistant genes and their insertion in to appropriate cultivars, isolation and insertion genes for protection of plants against rootworm and cutworm and other pests and diseases, development of improved root structures etc. Insect resistant and stress tolerant plants of diverse nature may be developed in a planned manner to address the needs of the specific agro-climatic regions. Transgenic animals with emphasis on high Feed Conversion Ratio need also to be developed. Since all these projects require large amounts of money, they must be initiated at the basic level in the several public-funded agricultural and other national institutes in the country with extensive foreign collaborations, where available.

“Invention” -selective and “Innovation” proneness: the backbone for survival

India has severe resource constraint. Tropical neglected diseases and some other factors are still responsible for sizable man-day losses; many such diseases pull back the country towards ill health, morbidity and even mortality. Malnutrition and iron deficiency are other neglected areas. Cheap and effective medicines are not available in many cases. Companies have considered investments in these areas, as economically unprofitable Investment is selected such areas should be deliberately pushed for conducting basic research and applications. Public funds and innovation-friendly policies can make inroads for more investment in these areas within the country.

Specific programs of basic and application-oriented research should also be initiated in agriculture and animal husbandry practices including fisheries as discussed earlier.

Innovation, which is the backbone for acquiring proficiency and an edge, has to take a quantum jump to enable India, to make significant contributions in the global context. In- house technologies for deployment shall not be many; imported technologies shall be expensive. Cutting edge technologies shall not be available for purchase. India realizes this and of late has started paying considerable attention towards developing its own technologies. Several strategies are being opted for, which include strengthening own R&D capabilities, teaming up with institutions and technology companies, buying / acquiring biotech companies that have core competence and the like. It is necessary to examine if these strategies adequately cover the vulnerability of the Indian biotech companies and the people to receiving abundant supply of modern biotech medicines at affordable prices and increased productivity in agriculture so as to keep up the availability of nutritious food and feed for the country.

Concluding Remarks
The scenario of biotechnology industry in India is going to be complex and multifarious. While there shall be considerable increase in the production of conventional biotech products including sera and vaccines, diagnostic devices and fermentation based therapeutic substances, the modern biotech products deploying recombinant DNA technology shall hover around patent expired therapeutics and diagnostics in the healthcare area. In agriculture, backcrossing by using GM plants containing specific genes borrowed from outside shall be used to develop GM plants of diverse nature. However, their acceptability to the common man will be a grey area till other countries, especially Europe come up to accept those in their commercial agriculture. In this context it is emphasized that one of the ways of raising productivity and reducing production costs is to use GM seeds. This factor cannot be lost sight of. On a priority basis, research on GM seeds in public-funded institutions must be pursued more vigorously; matured transgenic technologies be developed and kept ready for use in commercial agriculture. The present time shall change and soon societies shall look for GM technologies, when the preparedness shall come handy.

Government support especially in the form of providing seed capital shall encourage the expansion of new industries in the small and medium scale sector in several areas of biotechnology, specially in the healthcare area. Societal demand shall encourage the registration of high-tech new products, the technologies of which are developed outside India. Such products shall be expensive and it would not be easy for a common man to afford them. Therefore, cheaper substitutes have to be in place even though they might not be as effective. As the reimbursement of medical treatment costs is not liberal and adequate for a common man, the situation is likely to contribute to societal turbulence. A difference can be made only through appropriate planning, prioritization, action and implementation.

There is much turbulence ahead over a period of another four to five decades. There has to be perception for such turbulence and long-term steps must be taken to minimize its adverse affects to the people.