As Bush descends on the country, a number of events are planned to synchronise with his visit and mark its success. One amongst the many has a vital bearing on more than 60% of Indian population, namely the “Indo-US Knowledge Initiative on Agricultural Research and Education.” This is a follow-up of the understanding reached during Manmohan Singh’s US visit and the subsequently, the Indo-US Umbrella Agreement signed in October last year. The disquieting part of this knowledge initiative is that it is very clearly driven by Monsanto and Wal Mart from the US side. The US side has also made clear that any funding that comes to this initiative from the US side will be from the private sector and will be obviously tied to the US IPR laws.

The Indian side may hark back to the green revolution and the role that the US land grant universities played in it. The world has changed since then and the key element of this change in the realm of agriculture is that unlike the science of green revolution that came from public domain science, today’s gene revolution depends almost entirely on private domain science. This means that if we harness Indian scientific research to the US, then it is allowing the complete dominance of companies such as Monsanto on Indian agriculture. If the future of Indian agriculture lies in biotechnology, as the Indian Government believes, then allowing US MNCs to dominate Indian agricultural research would be the worst outcome for Indian farmers.

Coupled with this attempt to yoke Indian agricultural research to the US private bandwagon, is the attempt to sell a model of a completely corporatised agriculture. Manmohan Singh and Montek Ahluwalia have been talking about the need to bring in private capital in a big way in Indian agriculture as the only solution to the agrarian crisis in the country. We will not go in the details of this vision, but will only note that corporatising agriculture will do little to help the bulk of the rural population. With its focus on commercial crops, bulk procurement and retail chains, such corporatisation can only weaken the small farmer even more. Already in Punjab, corporate interests such as Monsanto, Reliance and others are making a beeline for agri-retail trade. With gradual withdrawal of the Government from procurement, more and more of retail trade for agriculture is going pass into these hands.  The presence of Wal Mart on the US side also makes clear the interest that the US has in opening India’s internal and external trade in agriculture to US companies.

The first Green Revolution grew from an international public research system that began in the 1940s and built up a chain of research centres worldwide. These centres collaborated through the Consultative Group on International Agricultural Research (CGIAR), a consortium of donors including foundations, national governments, United Nations institutions, etc. These centres operated in a world without Intellectual Property Rights and distributed seeds and new varieties all over the world. The striking improvements of yields in a number of crops, particularly wheat, rice and maize came out of this open institutional structure of science and research.

The key difference today from the green revolution days is that agricultural research has now been largely privatised in the US. Even the university system in the US today operates with the patents being licensed to private parties. This is a fundamental shift in science that has taken place. Earlier, all advance stemming from publicly funded research was supposed to be in the public domain. However, in the US, it changed with the Bayh Dole Act of 1984 that allowed knowledge created by public funding to be patented. This has been followed in most countries with public institutions joining the private sector in the rush for patents. The problem here is that such patents held by public institutions are not used for public good but in turn are licensed to private companies. The university or the public institution may get a large revenue as a result, but the public does not get any benefit to this public funding of such research.

Therefore, even the institutions that helped in the first green revolution are pursuing a different agenda today. They are so closely tied up with agribusiness in the US that instead providing help to our agricultural research, they are more likely to be allied with US big agribusiness.

The other major shift that has taken place in agriculture is that before the 80’s, the only protection available for plants were plant breeder’s rights. However, since then the US has followed an aggressive policy of patenting micro-organisms, life forms, seeds, genes and even gene sequences. This is the route that other countries are also following, particularly after the WTO/TRIPS agreement of 1994. TRIPS forces IPR protection for micro-organisms and allows countries to introduce life form patenting. A recent survey published in Nature, found that about three-quarters of plant DNA patents today are in the hands of private firms, with nearly half held by 14 multinational companies; virtually no such patents existed before 1985.

Let us take the current biotechnology advances in creating new varieties of plants. The major thrust of creating new varieties is to introduce new traits by transferring genetic material from other species. This is why such varieties are called transgenic (more commonly genetically modified organisms or GMOs).  The two main processes for transferring genetic material across species is to use a soil bacteria, Agrobacterium tumefaciens as a vector for transferring genetic material or to use the gene gun. Agrobacterium is a soil bacteria that introduces some of its own genetic material in the infected plant causing tumours or gall in the plant. Agricultural scientists have modified the bacteria and can use it as a carrier for other genes to incorporate novel traits of other species. The gene gun sprays the genetic material and thus can be used to insert genes from one species to another.

Both the above procedures are covered by a variety of patents. Cornell University holds the patents on the gene gun which in turn it has licensed it to Du Pont. Monsanto and a few companies hold the patents on the use of Agrobacterium and thus make it difficult for any transgenic variety to be developed without infringing their patents. Although much of the basic research that led to Agrobacterium-mediated transformation was done in public institutions, the private sector now holds many of the key patent positions, either through internal research and development, or from public institutions in the form of licenses.

 A simple case of trying to use genetically modified organisms for public good is that of the much-touted golden rice, which incorporated beta-carotene as a source of Vitamin A. It is subject to at least 40 patents and only after a major international effort could its use in public domain be permitted. The current patent landscape effectively seals the potential of using it for the small and medium farmers in developing countries. They simply cannot pay the cost of intellectual property that is being claimed by the agribusiness companies such as Monsanto.

We have already written extensively on IPR issues in these columns earlier. This article is not simply to repeat the dangers of the current IPR regime. That does not need any reiteration. What we are bringing out here is that by tying India’s agricultural research to Monsanto and other agribusiness companies, we are effectively sealing other avenues of development.

Are there other options available to Indian agricultural research? No one denies the strength of Indian science today. Indian agricultural scientists number 7,000 and another 40,000 are involved in the extension program. What other avenues exist to use this strength in the interests of our agriculture?

One of the most exciting developments in biotechnology today is the development by a group of scientists – a multi-country initiative called Cambia  -- of Transbacter for transferring genetic material, as an alternative path to that of Agrobacterium. It is not the actual technical advance that is important but the model of science used. This group decided that the current model of IPR protected biotechnology is against the interests of the farmers and it is necessary to provide in the public domain alternatives to such patent protected technologies. They explicitly modelled themselves on the Free Software/Open Source Software paradigm and now Transbacter, effectively have broken the monopoly of Monsanto and others private companies. The Cambia initiative does not do away with patents; what it does is to put this patent in public domain and ensures that any process that uses Cambia’s patent also has to be put in public domain.

Cambia’s development of Transbacter as an alternative to the Agrobacterium route has been hailed as a major technological achievement in itself. While Monsanto and others did make some initial noises of examining whether Cambia is violating any of their patents or not, it is now clear they have thrown in the towel. Cambia had in fact looked at all the current biotechnology patents and found that if an alternative to Agrobacterium exists, the rest of the patents could be circumvented: most of these patents stood on the narrow base of this specific gene transfer vector. But more than the scientific achievement itself, it is the vision of scientists joining worldwide in a co-operative venture to develop public domain science that provides the excitement around the Cambia initiative.

China has taken a different route in ensuring that their agriculture does not succumb to the seed MNCs such as Monsanto. They have bought some crucial patents from smaller companies in Japan and other countries and have developed their own GM products. Bt Cotton and Bt rice in China are from their public sector scientific institutions and operating on the same principles that green revolution did.

One of the major challenge that genetically modified plants face is that no country can afford to give up its independence and surrender its agriculture to Monsantos of the world. Unfortunately, if the scientists across the globe are banding together to develop public domain science, the Indian science establishment, under the Mashelkar-Montek Singh aegis is tying up to the apron strings of global private capital.

The Umbrella Science Agreement signed between Kapil Sibal and Condoleeza Rice last October has yet to be made public. We do not know what are the terms of this agreement. All we know is that in 1993 a similar agreement collapsed on IPR issues. The nation would like to know what has changed in the Indian position since then which make the IPR issues raised earlier no longer valid? Why is it that this agreement is still being kept secret? Are the IPR terms of the Agreement in conformity with our patent laws where no life form can be patented? How has micro-organism been defined? Or has micro-organism being defined in a way that genes and gene sequences can also be patented? The country has a right to know these issues before any grandiose agricultural knowledge initiative is signed between the US and India.

If the British conquered India using Indian soldiers, this Government seems eager to provide similar services to the US. In today’s knowledge world, instead of soldiers, the US requires Indian scientists. The knowledge initiative seems to be tailored to this purpose. A sad day indeed for Indian science when the very institutions set up to develop Indian agriculture are used to subvert it.

IT has been argued that if cereals – rice, wheat, corn, maize, etc --- had not been cultivated by man, human civilisation may not have existed in the form we know today. Settled agriculture was crucially dependant on the cultivation of cereals, all of which are believed to have descended from a wild grass that existed over 50 million years ago. Over millions of years, the earth has seen the evolution of crops like rice, wheat and corn that we are familiar with.
Rice has been cultivated by humans since the Neolithic era or late stone age, which started some 10,000 years ago. Human intervention has refined the many varieties of cereals through selective breeding. Now we have the tools to immensely increase our knowledge about the commonest cereal on earth – rice.

RICE GENOME MAPPING UNDER THE AEGIS OF IRGSP

The science journal Nature, recently announced the successful mapping of the rice genome by an international team working in tandem under the aegis of the International Rice Genome Sequencing Project (IRGSP). The IRGSP is a consortium of publicly funded laboratories, established in 1997 to obtain a high genetic mapping of the rice genome using the variety called Nipponbare – a rice variety of the sub-species japonica that is grown in Japan and temperate regions of Europe. The consortium is currently comprised of ten members: Japan, the United States of America, China, Taiwan, Korea, India, Thailand, France, Brazil, and the United Kingdom. The team was led by Japan, where some of the preliminary work had already been done before commencement of the Project in 1997.

Mapping of a genome means knowing the sequence and number of genes that contain all the genetic information of a particular organism. This genetic information is present in all cells of a living organism in the form of codes that are made by the arrangement of 4 basic building blocks – in plants these building blocks are four complex sugars called adenine, thymine, cytosine and guanine. These building blocks are arranged in particular sequences in the DNA of each cell of a living organism. A number of pairs of these blocks form a single gene – which is responsible for regulating a particular characteristic of the organism by regulating the production of specific proteins. All the genes in an organism put together are called the genome. The mapping of the rice genome is the largest exercise of genome mapping undertaken, larger even than the mapping of the human genome that was accomplished a few years back – again by a consortium of public funded laboratories. In fact the accuracy and coverage of the mapping in the case of the rice genome is believed to be of higher quality than the human genome mapping.

THE IMPORTANCE OF RICE GENOME

There are several reasons why the mapping of the rice genome is being seen as something of a landmark. The first reason has to do with the importance of rice as a source of food in the world. Rice provides 20 per cent of the world's dietary energy supply, while wheat supplies 19 per cent and maize 5 per cent. Rice represents 30 per cent of global cereal production today, and production levels have doubled over the past 30 years. 3.2 billion people, i.e. about half of the present population of the world consume rice as the principal source of calories that provide them with energy. While 89 countries in the world grow rice, 90 per cent of rice is consumed in Asia. In Africa there is a major move to switch to rice from other traditional cereals – thus rice is the staple food for a majority of poor people in the world. Current consumption trends suggest that about 4.6 billion people will be reliant on rice by the 2025.

Another reason for choosing rice for genome mapping was that the rice genome is by far the simplest among all major cereals -- six times smaller than that of corn and 37 times smaller than that of wheat. Rice plants have 12 chromosomes containing about 37,544 different genes, which are in turn made up of about 389 million base pairs (i.e. pairs of the basic 4 building blocks) of DNA. By comparison, corn has 3 billion base pairs. It still is a more complex genome than the human genome which has about 20,000 known genes arranged in 24 chromosomes.

Not only is the rice genome the simplest, it is also in many ways the basic framework for the genomes of other cereals. Thus mapping of the rice genome will also help in understanding and subsequent mapping of the genomes of other cereals.

BENEFITS OF THE GENOME MAPPING

The key issue however is, what benefits are expected from the mapping of the rice genome. To understand this we need to understand something about the rice plant. The plant is abundant in nature – and there are an estimated 120,000 varieties in nature – most of which are non-cultivated wild varieties. In spite of its abundance and large diversity of species, the plant has a number of problems. Typically the rice plant is extremely dependant on water – over 5,000 litres of water are required on an average to produce 1 kg of rice. It is also incapable of withstanding low temperatures. Thus the cultivation of rice is difficult in water scarcity areas and in colder climates. With global warming projected to increase the incidence of drought years in the future, this problem could accentuate over the years. Hybrid varieties of rice which can withstand more difficult conditions are more difficult to develop than say wheat. As a consequence the growth in rice production that averaged about 4 per cent till the 1960s has now dipped to 1 per cent --- that is much below the rate of growth of population of those who consume rice. Further, despite the widely prevalent use of rice as a staple, rice is also a deficient food in some ways. It is deficient in Vitamin A and iron. Rice actually produces a chelating compound, phytic acid that takes iron out of the diet.

Mapping of the rice genome provides the tools to create varieties that address many of these problems – high yielding, less water dependant, disease resistant, and more nutritious. New varieties that are created using the knowledge now available through the mapping of the genome do not necessarily have to be varieties that are transgenic – i.e. varieties that are created by introducing genes of other plants into the rice plant. This is important to understand as the development of transgenic varieties have been mired in controversy. Some years back the introduction of “golden rice” which contained genes from the daffodil plant to induce Vitamin production in the rice plant, was opposed by many quarters. While techniques for genetic manipulation make progress many of the technological problems and dangers of creating transgenic varieties are likely to reduce appreciably. But the mapping of the genome allows manipulation of the rice plant even without going the transgenic route.

The genome map provides vital information about the rice plant which can be used to improve rice varieties by techniques that do not involve introduction of “foreign” genes. For example, rice already produces provitamin A, but as it is present in the husk, it is removed when rice is processed (traditional method of parboiling in India is in fact designed to retain the Vitamin A from the husk). With knowledge of the genome, it should be possible to coax this gene to produce provitamin A in the seed without using transgenic technologies. Already, researchers in Japan, using the new map, are hot on the trail of genetic variations that might allow rice to grow in colder climates, while research in the Philippines is progressing on strains that could yield enough even in drought years to keep a farm family from starving.

The mapping of the rice genome could also have another useful fallout. Knowledge of the rice genome will help greatly in the search for useful traits carried by in the collection of a huge number (almost a 100,000) of traditional varieties and wild species of rice managed by the International Rice Research Institute. It could result in increased interest in the genetic diversity of rice and could help raise public awareness about the loss of genetic diversity caused by abandoning traditional varieties in favour hybrids. The development of rice genomics can make it easier the transfer of advantageous traits to locally adapted varieties.

In addition of course, knowledge of the rice genome helps unravel the genomes of other cereals. All cereals are close genetic relatives, and rice, with the smallest genome, proved to be the easiest to analyze. It is a crucial model for understanding the biology of all cereals.

MONSANTO AND SYNGENTA JOIN THE BANDWAGON

The story of the mapping of the rice genome would be incomplete without a mention of a parallel exercise to the Project that was carried out by two giant biotech companies. In 2000/2001 two of the largest Biotech companies in the world – Monsanto and Syngenta – separately and in quick succession announced that they had mapped the rice genome. They also announced that they were willing to co-operate with the International Rice Genome Sequencing Project and share some of their findings. The first question that arises is that if these two had already mapped the rice genome, why was it necessary for the international project to continue. And second, why did they agree to co-operate with the public funded Project.

The answer lies in the fact that the Monsanto and Syngenta “maps” were actually rough “drafts” - much poorer in accuracy than what the international project produced. For example, international Project demarcated 6756 genes on chromosome 1, whereas Syngenta only reported 4467, of which half of those predicted did not have a complete coding sequence. If the two companies had on their own produced accurate mappings, it would have been a disaster for research on rice varieties. The two would then have ensured that none of the information would be available in public domain – the international Project is committed to putting all its information in public databases. But because they realised that their maps were not good enough, they offered to cooperate so that they could also use the final product for their own needs.

Further, it must also be understood that Monsanto and Syngenta are not really interested so much in rice – the poor man’s staple. But their crude draft is sufficient for them to characterise the genes which are of economic interest in other cereals, using rice as a basis. Their interest lies in crops like corn and wheat – the rich man’s staple consumed in North America and Europe.

In the final analysis the mapping of the rice genome marks another triumph of public funded research. However tangible benefits will take time to accrue – in some cases over a decade. It is hoped that these benefits too will be available in the public domain just as the genome map is now available in public domain. It would be a great pity if the likes of Monsanto and Syngenta were to appropriate the public domain knowledge for their private gains.

RESEARCH on stem cells has been in the news in recent times for very contradictory reasons. On the one hand, it raises visions of a constant supply of living material that can repair and replace almost any diseased or ageing portion of the body. Sounds like something from a science fiction novel, but is today within the realms of possibility. On the other hand, it is being attacked by the conservative establishment in the US, led by George Bush, as immoral and horrific. Whatever the resolution of the debate, the genie is out of the bag and stem cell research is here to stay.

WHAT IS STEM CELL RESEARCH?

Advances that help us understand the way cells in our body function have opened up a this new area of research. These advances now point to the potential of using the human body's own cells to repair defects in the body that lead to disease. Interest in this regard is centred around what are called stem cells. These are cells from the human body that have still not become specialised in their function, i.e. they have not formed into cells in the muscle, or skin, or intestines, or any other part in the body performing a specific function. These cells are thus called "pluripotent" i.e. they have the potential to develop into any kind of cell with a certain specialised function.

Stem cells have two important characteristics that distinguish them from other types of cells. In addition to being unspecialised cells, they react to and certain "triggers" that induce them to become cells with special functions. Research is being conducted on two kinds of stem cells from animals and humans: embryonic stem cells and adult stem cells.

Stem cell research is not really new -- ways to obtain stem cells from mouse embryos were discovered more than 20 years ago. However the major advance came in 1998 when methods to isolate stem cells from human embryos and grow the cells in the laboratory were discovered. These are called human embryonic stem cells. Human embryos are now routinely formed by the fertilisation of a human egg by a sperm under laboratory conditions. The method is used to treat infertility in couples. Normally the number of embryos formed for a couple is much larger than required to induce pregnancy, and these can be used as a source of embryonic stem cells.  Stem cells can be harvested from a 3-5 day old embryo, called a blastocyst. In the US a lot of opposition to stem cell research centres around the use of human embryos, and the "anti-abortion" and "pro-life" lobbies have been in the forefront in the campaign against stem cell research. However it needs to be understood that stem cell research does not use developed human foetuses but microscopic embryos that are artificially created in the laboratory.

Stem cells are also found in the adult body, in different organs like the bone marrow, brain, etc. These cells remain non-specialised for years and start to become specialised in function to repair some damage or to replace old specialised cells that die out. These are called adult stem cells.

These stem cells, later in life, give rise to the multiple specialised cell types that make up the heart, lung, skin, and other tissues.  Scientists are now engaged in determining how stem cells remain unspecialised and are able to multiply for many years and also in identifying the signals that cause stem cells to become specialised cells. The interest lies in the fact that if this can be done, the cells can be artificially introduced into the body to repair damaged organs, viz a damaged heart, or brain, or liver – the potential is virtually unlimited.

Unlike specialised cells like muscle cells, blood cells, or nerve cells --- which do not normally replicate themselves --- stem cells may multiply as exact copies of the original (replicate) many times. When cells replicate themselves many times over it is called proliferation. A starting population of stem cells that proliferates for many months in the laboratory can yield millions of cells. If the resulting cells continue to be unspecialised, like the parent stem cells, the cells are said to be capable of long-term self-renewal. One key area of research is to understand the signals in a mature organism that cause a stem cell population to proliferate and remain unspecialised until the cells are needed for repair of a specific tissue. Such information is critical for scientists to be able to grow large numbers of unspecialised stem cells in the laboratory for further experimentation.

When unspecialised stem cells give rise to specialised cells, the process is called differentiation. Scientists are just beginning to understand the signals inside and outside cells that trigger stem cell differentiation. The internal signals are controlled by a cell's genes. The external signals for cell differentiation include chemicals secreted by other cells, physical contact with neighbouring cells, etc.

However, many questions about stem cell differentiation remain. For example, are the internal and external signals for cell differentiation similar for all kinds of stem cells? Can specific sets of signals be identified that promote differentiation into specific cell types? Addressing these questions is critical because the answers may lead scientists to find new ways of controlling stem cell differentiation in the laboratory, thereby growing cells or tissues that can be used for specific purposes.

ADULT STEM CELLS

Attention is now also turning to the use of adult stem cells. Adult stem cells typically generate the cell types of the tissue in which they reside. A blood-forming adult stem cell in the bone marrow, for example, normally gives rise to the many types of blood cells such as red blood cells, white blood cells and platelets. Until recently, it had been thought that a blood-forming cell in the bone marrow -- which is called a hematopoietic stem cell -- could not give rise to the cells of a very different tissue, such as nerve cells in the brain. In fact, adult blood forming stem cells from bone marrow have been used in transplants for over 30 years.

The history of research on adult stem cells began about 40 years ago. In the 1960s, researchers discovered that the bone marrow contains at least two kinds of stem cells. Around the same time, scientists discovered that regions in the brains of rats contained dividing cells, which become nerve cells. However, for a long time, most scientists continued to believe that new nerve cells could not be generated in the adult brain. It was not until the 1990s that scientists agreed that the adult brain does contain stem cells that are able to generate the brain's three major cell types.

A number of experiments have suggested that certain adult stem cell types are pluripotent. This ability to differentiate into multiple cell types is called plasticity or transdifferentiation. Hematopoietic stem cells in the bone marrow may differentiate into: three major types of brain cells (neurons, oligodendrocytes, and astrocytes); skeletal muscle cells; cardiac muscle cells; and liver cells. Similarly bone marrow stromal cells may differentiate into cardiac (heart) muscle cells and skeletal muscle cells and brain stem cells may differentiate into blood cells and skeletal muscle cells. Current research is aimed at determining the mechanisms that underlie adult stem cell plasticity. If such mechanisms can be identified and controlled, existing stem cells from a healthy tissue might be induced to repair a diseased tissue.

COMPARATIVE ADVANTAGES

Human embryonic and adult stem cells each have advantages and disadvantages regarding potential use for cell-based regenerative therapies. Embryonic stem cells can become all cell types of the body because they are pluripotent. Adult stem cells are generally limited to differentiating into different cell types of their tissue of origin. However, as discussed earlier, we now know that some adult stem cell can exhibit plasticity. Another difference is that, while a large number of embryonic stem cells can be grown in a culture medium, adult stem cells are rare in mature tissues and methods for culturing them in large numbers are yet to be standardised. A potential advantage of using stem cells from an adult is that the patient's own cells could be expanded in culture and then reintroduced into the patient. The use of the patient's own adult stem cells would mean that the cells would not be rejected by the immune system. This represents a significant advantage as immune rejection (where the body's immune mechanisms fights and kills cells from a different organism) is a difficult problem one would encounter if embryonic stem cells are introduced into a person. The "rejection" can only be circumvented with immuno-suppressive drugs which have other toxic side-effects.

POTENTIAL APPLICATIONS

There are many ways in which human stem cells can be used in basic research and in clinical research. But it must be understood that there are still many technical hurdles between the promise of stem cells and the realisation of these uses. Studies of human embryonic stem cells may yield information about the complex events that occur during human development. A primary goal of this work is to identify how undifferentiated stem cells become differentiated. Scientists know that turning genes on and off is central to this process. Some of the most serious medical conditions, such as cancer and birth defects, are due to abnormal cell division and differentiation. A better understanding of the genetic and molecular controls of these processes may yield information about how such diseases arise and suggest new strategies for therapy. Scientists, however, are yet to fully understand the signals that turn specific genes on and off to influence the differentiation of the stem cells.

Human stem cells could also be used to test new drugs. Today human volunteers are used to test for safety and efficacy of new medicines. In the future new medicines could be tested on cell cultures obtained from stem cells in a laboratory. Thus, for example, a medicine to treat a heart condition could be tested on cells artificially grown in a laboratory and made to differentiate into heart muscle cells. Scientists still need to be able to precisely control the differentiation of stem cells into the specific cell types on which drugs will be tested.

Perhaps the most important potential application of human stem cells is the generation of cells and tissues that could be used for cell-based therapies. Today, donated organs and tissues (for example, in case of heart, kidney, cornea or liver transplant) are often used to replace ailing or destroyed tissue, but the need for transplantable tissues and organs far outweighs the available supply. Stem cells, directed to differentiate into specific cell types, offer the possibility of a virtually unending source of replacement cells and tissues to treat diseases including Parkinson's and Alzheimer's diseases, spinal cord injury, stroke, burns, heart disease, diabetes, osteoarthritis, rheumatoid arthritis, blindness, kidney or liver failure, etc.

For example, it may become possible to generate healthy heart muscle cells in the laboratory and then transplant those cells into patients with chronic heart disease. Preliminary research in mice and other animals indicates that bone marrow stem cells, transplanted into a damaged heart, can generate heart muscle cells and successfully repopulate the heart tissue. Other recent studies in cell culture systems indicate that it may be possible to direct the differentiation of embryonic stem cells or adult bone marrow cells into heart muscle cells.

Similarly, in people who suffer from diabetes, the cells of the pancreas that normally produce insulin are destroyed by the patient's own immune system. New studies indicate that it may be possible to direct the differentiation of human embryonic stem cells in cell culture to form insulin-producing cells that eventually could be used in transplantation therapy for diabetics.

It may be noted from this discussion that research on stem cells is a far cry from what many believe it to be - human cloning. No serious researcher on stem cell research is engaged in producing a whole human being from stem cells. Rather the effort is to standardise the method of producing cells in the laboratory that can perform specialised functions. It is an exciting area of research today and has enormous potential.

RECENTLY the leading Indian pharmaceutical company Ranbaxy and the leading global pharmaceutical major, Glaxo Smithe Kline announced that they had come to a collaborative agreement on pharmaceutical R&D. This agreement is being hailed in industry circles as an example of the strides that pharmaceutical R&D in India has made in recent years, and also that the deal signifies how the new patent regime that allows Product Patents will actually benefit Indian companies.

ONE SIDED DEAL

Details about the deal are not available, but the companies announced that the they have entered into a drug discovery and clinical development collaboration covering a wide range of therapeutic areas. In a joint statement announced on October 22, the two companies announced that several collaborative scenarios are envisioned, with Glaxo and Ranbaxy leveraging their respective resources and expertise. Ranbaxy will be responsible for activities from optimisation of a lead compound to generation of a development candidate. Leads may be provided by either Glaxo or Ranbaxy. For a proportion of the candidates selected within the collaboration, it is expected that Ranbaxy will conduct early clinical work. Glaxo and Ranbaxy will form an Executive Steering Committee to oversee the research. Once a compound has been selected as a development candidate, in most instances Glaxo will complete development. Glaxo will have the exclusive commercialisation responsibilities worldwide, while Ranbaxy will take the lead in India.  Ranbaxy, with the consent of Glaxo may co-promote in EU and US. The financial terms of the agreement were not disclosed.

For Glaxo, a major benefit of the deal would be to accelerate the development of new products at lower cost. Ranbaxy’s head of research, Rashmi Barbhaiya said after the deal that for Ranbaxy, “This is a classical example of a company making a transition from a re-engineering company to an engineering company.” Some would say that this is a “win-win” situation for everybody. But a closer look at the deal would show that things are not as simple as it would appear at first glance.

Clearly, in the deal, Ranbaxy is the junior partner. The global rights would be retained by Glaxo. Also while Ranbaxy will develop the initial identification of “promising molecules” i.e. drugs that seem to have a potential for further research to be conducted, Glaxo will complete the final development. What does this really mean? It means that in the pharmaceutical sector too, as is happening in the Information Technology (IT) Sector, India will become a haven for “outsourcing” of some elements of drug development.

Cheap Indian technical human-power will be used to do the less technology intensive work while MNCs will still control the fruits of this research.  Let us remember that this deal involves Ranbaxy, the largest Indian pharmaceutical company. It is extremely unlikely that other Indian companies will be able to negotiate deals with MNCs that offer better terms. The trajectory of Indian companies after the WTO agreement on Patents comes into force, thus becomes clear. Some companies like Ranbaxy will tie up with MNCs as junior partners. Others will face immense competition from MNCs in the coming years and many of them may be forced to close down. The Indian market itself, which today is dominated by Indian companies, will thus be prised open for MNCs to exploit - either directly or through their Indian partners. In return the only carrot that is being dangled in front of some Indian companies like Ranbaxy, is that they may be allowed a share of the global market - but at terms set by the MNCs.

Let us remember that the TRIPS agreement on patents was essentially designed to address the threat posed to MNCs by drug companies from the developing world - India, Brazil, Thailand, China, etc. The Ranbaxy-Glaxo deal brings home how the TRIPS agreement is converting the competitors into collaborators!

Today Indian companies like Cipla are offering drugs to treat AIDS at one-thirtieth or less of the prices that were being charged by MNCs. Faced with such competition MNCs too have been forced to reduce and negotiate the prices that they charge. In the post TRIPS world this will become impossible as MNCs  “buy out” potential competitors.

Before the Patents Act was amended legitimate doubts had been expressed that this would result in our indigenous R&D base (related almost entirely to development of process technologies) redundant. We are now seeing that these fears were entirely justified. In the changed situation, where the government has decided to move towards a Product Patent regime, a whole new R&D plan is required for the industry. In such a revised R&D plan public funded R&D - through CSIR labs - has to play the key role. There is no short cut to building of an R&D base, as experiences all over the world have shown. This is true not only in the pharmaceutical sector but in all sectors of the industry. Even in the US today, a large portion of basic research is conducted through public funded R&D. Strengthening of public funded R&D should, of course, go hand in hand with the building of links between public R&D institutions, universities, etc and the industry.

WORLD CLASS FACILITIES REQUIRED

It is unfortunate that in the period since 1970, little or no infrastructure for Product R&D was built up in the country, either by the government or in the private sector. Product technologies require a different kind of R&D infrastructure. Only a part of the R&D expenditure is related to the development of the new molecules. In the case of process technologies, since the drugs under development have already been subjected to toxicity, efficacy, animal and human trials, little infrastructure is required to conduct such trials. In the case of product development a crucial element of the R&D infrastructure is related to the facilities required for such trials. In order for the products to be competitive globally, such facilities need to be world class.

A major constraint for the drug industry in India is the relatively small domestic market (compared to our population). The solution to this constraint cannot be sought within the industry, as it has to do with the extremely low purchasing power of over 80 per cent of our population. Product development in the pharmaceutical sector is estimated to cost around Rs 2500 crore (for a single product) over a period of 10-12 years in developed countries. This is in a situation where there already exists an infrastructure for basic R&D in Product development. Even if we consider a lower figure of Rs 1000 crore (if we assume that R&D costs will be lower in India) and for the sake of argument not consider the lack of existing infrastructure, it still means an annual expenditure of Rs 100 crore. This figure is equal to about 20-25 per cent of the total sales of the largest Indian company. It should be evident that such a jump in R&D expenditure is not possible for any drug company in India to even consider. Let us remember that these projections are for a hypothetical situation where a single product is to be developed. It is well known that less than 10 per cent of “promising” molecules actually make it to the market. Further only a fraction of those that reach the market are commercially viable. It is precisely because of such a situation that opponents of the Amendment to the Indian Patents Act have argued that the stage of industrial development in the country is best served by a Process Patent regime. However, if we are to continue on the course towards a Product Patent regime, no amount of sops to privately funded R&D can contribute to a Research plan for the drug industry. R&D activities for product development can be “kick-started” only through large funding for public funded R&D. Any R&D plan needs to first internalise this fundamental issue.

If this is not done we will see our large pharmaceutical companies being pushed into the lap of MNCs - as we see happening in the Ranbaxy-Glaxo deal.

NEED TO LEVERAGE ON OUR ADVANTAGES

In spite of the constraints mentioned earlier, India (with the possible exception of China) is the only country in the Third World that can conceive of a programme for product development. India has a fairly large domestic market, indigenous manufacturing capability, a large pool of S&T personnel, and a dispersed R&D infrastructure (albeit for process technologies). We also have an advantage over developed countries, in that our personnel and infrastructure costs are a fraction of costs in these countries. It is possible for us to leverage on these advantages, but for us to be able to do so a cogent research plan is required. Since the scale of funding required for product development appears to be too high for individual companies to sustain, new mechanisms need to be developed.

One possible mechanism could be a cooperative structure, with participation from the industry and government, for conducting animal and human trials and for generating efficacy and toxicity data. A major component of costs for product development are incurred in these areas. Only a pooling of resources can lead to the building up of such an infrastructure. The solution lies in such a cooperative exercise and not in disbursing disparate amounts to individual companies.

If we do not do this, the private sector may feel satisfied in acting as R&D subsidiaries of large MNCs. The advantage that we have will then be utilised by MNCs in the form of cheap S&T manpower and low infrastructure costs. But such a route will not result in the building of an independent R&D base. This is what we see happening in the software industry where multinational software companies are using cheap Indian labour to develop products that are patented in their home countries, without contributing to the development of an R&D base in the country. There is a danger of repeating this misadventure in the drug industry, unless public funded institutions play a leading role in setting up our R&D infrastructure. These institutions had done so in the case of development of process technologies, and there is no reason to believe that we cannot do it again in the case of product technologies, provided we do not seek short-term solutions.