[img_assist|nid=143|title=|desc=|link=none|align=right|width=100|height=43]Vitamin A deficiency (VAD) is a serious form of malnutrition that weakens the immune system and may cause blindness. Several measures address VAD and have shown positive results. Genetically modified rice containing beta-carotene is a new approach in an early experimental stage. Golden Rice demonstrates the problems of public research in an area where both plant and technology are heavily protected by patents.

While 800 million people are classified as undernourished Malnutrition stems from the poor distribution of food sources at global and household levels. Micronutrient deficiencies are most prevalent where there is poverty, environmental deprivation and social disparity.
Vitamin A deficiency (VAD) can lead to total blindness in children and to night blindness. Currently about 350,000 children become partly or totally blind each year due to VAD and about 60 per cent of them die within a few months after going blind. Although most children affected by VAD between 140 and 250 million . present only subclinical manifestations, they are likely to be more severely affected by measles, tuberculosis, diarrhoea and other illnesses and thus have a higher mortality risk. The World Health Organization (WHO) estimates that the elimination of VAD could reduce childhood mortality by 25 per cent. VAD is also common in pregnant women and exposes them to a higher risk of death during or shortly after delivery.

Available supplies of vitamin A are determined by three different factors. First, food intake in general, second its (pro-)vitamin A content, and third bioavailability and bioefficacy.

Vitamin A (retinol) is only present in animal products, but its predecessor beta-carotene or pro-vitamin A is found in orange fruits and roots or green leafy vegetables like carrots, sweet potato, cassava, mango or red palm oil( see box). Unfortunately, beta-carotene and vitamin A are not taken up easily from digested food because they are fat-soluble. Their so-called bioavailability, therefore, depends on the presence of fat or oil in the same meal, otherwise they are excreted undigested.

The FAO/WHO recommend a daily intake of 500 to 850 micrograms (mg) of vitamin A for adults and 400 mg for a child between the age of 1 and 3 years. This level of intake is set to prevent clinical signs of deficiency and to allow normal growth. Beta-carotene has to be converted into vitamin A in the body, and most studies estimate that about 6 mg beta-carotene make 1 mg of vitamin A (bioefficacy). Newer studies suggest that this ratio has been grossly underestimated and that it may be as high as 1:12, or even 1:15 or 1:21. This translates into a recommended daily allowance (RDA) of between 6000 and 10,200 mg beta-carotene.

Most countries with clinical VAD are located in South and Southeast Asia and sub-Saharan Africa. Due to the high population density, the largest numbers of persons affected by VAD are living in South and Southeast Asia. Severe VAD is also found in refugee settlements and amongst displaced communities.

Combating VAD

The elimination of VAD by 2001 was the goal adopted by the United Nations. World Summit for Children in 1990 and was reiterated by the FAO/WHO International Conference on Nutrition in 1992. Progress has been made since then. The WHO reported that the number of young children with total blindness has fallen by about two-thirds in the past 20 years and the United Nations Children. s Fund (UNICEF) estimated a 40 per cent decline in VAD prevalence between 1988 and 1998. Some countries, including Indonesia, Vietnam and the Philippines, have virtually eliminated total blindness in recent years.

Nevertheless, VAD is still a public health problem in 96 countries, mainly in Africa and Southeast Asia, and it often occurs in situation of malnutrition crises caused by wars or natural catastrophes. Most of the affected countries have submitted data to the WHO. However, the WHO reports that the governments of some 30 countries where VAD is prevalent have not implemented comprehensive plans to solve the problem. Some have not yet evaluated the problem and others have only just started to do so. The WHO, therefore, considers eradicating VAD as . a test case of political will, and managerial capacity to implement known technologies and known solutions.

Several short- and long-term measures exist to combat VAD:
General health care: Diarrhoea and parasites reduce the uptake of nutrients in general. Treating these conditions will therefore increase the vitamin A status of a person by reducing the body' s demand and losses. Vaccination against measles is also considered to improve the vitamin A status of a population.

Supplementation: The World Bank estimates that the delivery of a single capsule of vitamin A can be as low as US$ 0.02 when added to immunization efforts. Other programmes distribute capsules at schools. These measures do not offer a long-term solution especially because they will not reach very poor children who do not have the chance to go to school or have yet to start school. However, supplementation can be effective in emergencies or in specific short-term situations such as in cases where malnourished children have measles or for pregnant women who are fortunate enough to be within the reach of medical care. Recent studies show that weekly, low-dose supplements given to pregnant women can reduce maternal mortality by 50 per cent. Such treatment can also be targeted at other vulnerable groups like refugees.

Fortification: Butter, margarine and oil, but also sugar or biscuits can be fortified with beta-carotene, as has been done in industrialized countries for the past 70 years. This method requires cooperation with food processors and is only an option where people have regular access to processed food. Fortification can also recover a natural vitamin A content that was reduced during the processing of food. Dried skimmed milk, as it is exported for food aid programmes from the European Union and other countries, has added vitamin A so that milk made from this powder will contain similar vitamin A levels to those found in fresh milk.

Diversification and dietary education: A slow approach, but currently the most successful one, is the diversification of food and dietary education to those susceptible to hidden hunger. It requires diverse and locally adapted efforts as well as the cooperation of all stakeholders involved. The (re)introduction of local fruits and vegetables through the setting up of homestead production can provide a diet enriched by vitamins and other micronutrients. Other efforts include promoting breast feeding; collecting wild fruits, vegetables and mushrooms; hunting and fishing; raising livestock; and fish breeding. These projects are especially valuable because diversifying the diet in general can increase food security. Homestead production is an important option to supplement food in the context of the growing acreage of urban agriculture. Diversification of the diet is often complemented by dietary education. More beta-carotene is taken from a diverse meal than from a uniform one. Food-to-food fortification can be practised for example by mixing a tablespoon of carrots in a baby's rice porridge. Sun-dried fruits and vegetables that are seasonally available in surplus, or the drying of leafy vegetable to produce micronutrient-rich leaf flours can enrich food at other times of the year.

Plants with increased nutrient content: In food-based approaches varieties of plants are selected, bred or genetically modified (GM) to increase their nutrient content or their bioavailability or bioefficacy. Golden Rice is the first GM example and has gained such agressive media coverage that its potential is hard to judge at the moment. The president of the Rockefeller Foundation stated that the public relation uses of Golden Rice have gone too far. The industry. s advertisements and the media in general seem to forget that it is a research product that needs considerable further development before it will be available to farmers and consumers.

[img_assist|nid=179|title=|desc=|link=none|align=left|width=150|height=65]These different approaches can be seen as a continuum in which each is has advantages and disadvantages in particular situations. However, resources are limited and governments, organizations and institutes have to decide which options to favour. A number of issues have to be addressed: First, health benefits; second, costs to governments, donors and consumers; and third whether the approach is acceptable to those concerned in terms of culture and price, whether it is sustainable, equitable and environmentally sound, and whether there is sufficient community participation ensure that it is effective.

Golden Rice

In January 2000, Science published a paper about GM of rice (Oryza sativa) accomplished by Ingo Potrykus (Switzerland) and Peter Beyer (Germany), which is now being discussed as an approach to combat VAD. The rice is altered in such a way that beta-carotene is produced in the grains. Because of its yellow colour it became known as Golden Rice. Normally the outer layer of the rice grain, which is removed through polishing, contains a minimal amount of beta-carotene, but the actual grain, the endosperm, does not contain any.

[img_assist|nid=115|title=|desc=|link=none|align=right|width=150|height=65]Currently the GM trait is only expressed in trials in Swiss greenhouses in the japonica variety TP 309, which grows in a moderate climate. The trait has still to be tested in field trials under adequate, tropical conditions. Previous experiences with other GM plants have shown that GM traits are not necessarily stable when grown in the field and/or in different climate conditions. With Golden Rice, there is a genetic modification which, for the first time, consists of introducing multiple genes to turn a protein in the rice grain into beta-carotene. Unforeseen effects are more likely with Golden Rice than most GM crops where genetic modification consists of just a single gene construct.

If the GM trait proves to be stable in the field trials it will have to be introduced to other rice varieties either directly through GM or through crossing with the chosen varieties to develop varieties adapted to local conditions and with a sufficient beta-carotene production.

Breeding, new transformations and the biosafety assessment as planned by the International Rice Research Institute (IRRI, Philippines) will take at least three years.

These GM plants will be subject to the Cartagena Protocol on Biosafety (CPB) and be monitored under national regulations. Concern has been raised that the addition of beta-carotene could make Golden Rice more susceptible to different pests. Meanwhile nutritional tests will also be necessary to study whether the beta-carotene from the rice can be taken up in the intestine. These tests on bioavailability will have to take local cooking habits into account in the various local rice cultures.

In January 2001, samples of Golden Rice were delivered to the IRRI to begin research that will be part of an international programme to investigate its safety and its utility in combating VAD. Other public research institutes in Southeast Asia, India and China are to follow soon. Research in institutes in Latin America and Africa is planned for a later date. A technology transfer agreement about Golden Rice will probably be set up between Indian and Swiss scientists in 2001. Under the proposed agreement India would bear the cost of conducting studies, whereas about 50 grams of Golden Rice seed and the genetic constructs would be delivered from the Swiss side free of cost.

From research to patent

[img_assist|nid=143|title=|desc=|link=none|align=right|width=150|height=65]Even though Golden Rice is far from being introduced as food, it already shows an impressive history and challenges the possibility of public research in an area that is highly dominated by intellectual property rights (IPR) both in regard to the rice plant as well as to genetic engineering as a technology.

In 1992 Ingo Potrykus, university professor of the Swiss Federal Institute of Technology Zurich (ETH Zürich), started research on the production of beta-carotene in rice. He had been convinced since the 1970s that genetic engineering could contribute to food security. The research on rice was publicly funded by the Rockefeller Foundation from 1991 to 2002 (see also the interview with the Rockefeller Foundation), by the Swiss Federal Institute of Technology (1993-1996), by the European Union under a European Community Biotech Programme (FAIR CT96 1633, 1996-2000) and by the Swiss Federal Office for Education and Science (1996-2000). Through the contribution to another sub-project in the European Community Biotech Programme AstraZeneca (Sweden/ UK) was also involved.

Shortly after the publication of the scientific results, questions about the specific IPRs affecting product development arose. Potrykus and his colleagues had been using materials and technologies that are protected by patents for their research. That is in compliance with patent regulations, but the marketing of any product that is developed through such research falls under the claim of the patent owners who have the right to forbid the marketing of the product or to demand licence fees. In addition, the scientists used materials obtained from others under material transfer agreements (MTAs). Such agreements are set up individually in each case and can range from acknowledgement of material sources, to shares in later profit and restrictions on use. In spring 2000, it was unclear how many patents and MTAs were involved and under what conditions and/or licence fees the product Golden Rice could be marketed. At the same time the two senior scientists, Potrykus and his colleague made a patent application for Golden Rice.

According to Potrykus, he and his colleague were soon to realize that the task of technology transfer to developing countries, the international patent application, the numerous Intellectual Property Rights [...] we had used in our experiments, were too much to handle properly for two private persons. We urgently (because of the deadline for the international patent application) needed a powerful partner..

Greenovation (Germany), a spin-off company from the University of Freiburg, was founded in autumn 1999 to perform and fund research on biotechnology applications and to out-licence university research projects to life science companies. It applied for the patent, naming Potrykus and Beyer as the inventors and then facilitated an agreement with Zeneca, now Syngenta (Switzerland). Syngenta gained the exclusive rights on the Golden Rice technology in exchange for help with the IPR issues and the different testing of the rice for a humanitarian project. The rights to use Golden Rice free of a licence fee in a humanitarian project were to be granted back to Potrykus and Beyer. The scientists have been criticized for this deal because it gave away ten years of public funded research for a low price. They defended themselves arguing that public institutes lack the capacity to actually test and commercialize new products. The example raises important questions about the motivation behind private finance, which often seeks to recoup investment through sales. In the current situation of low consumer acceptance towards GM products, the added value of an increase of public acceptance might be sufficient for Syngenta. Nevertheless, it still has to be seen how big the actual input of Syngenta in the humanitarian initiative will be.

[img_assist|nid=185|title=|desc=|link=none|align=left|width=150|height=65]In Summer 2000, Monsanto, holder of numerous patents on rice as well as on genetic modification technologies, announced that they would grant royalty free licences on patents involved in the production of Golden Rice, even though at that point it was unclear how many patents this would include. Meanwhile the Rockefeller Foundation had commissioned a study to the International Service for the Acquisition of Agri-Biotech Applications ISAAA (USA) on behalf of IRRI to clarify the IPR issue and to advise IRRI on a strategy for the further development of Golden Rice varieties for developing countries.

The ISAAA study was officially published in autumn 2000 and lists more than 70 patents applying to the current form of Golden Rice across different countries. Because patents are country specific, not all 70 patents apply to all of the major rice producing, exporting, importing and consuming countries. The maximum of 55 patents applies in the USA, while in many of the developing countries between zero and ten patents are applicable. Among those with no applicable patents are top rice producers like Bangladesh and Thailand and main importing countries like Iran, Nigeria, Malaysia and South Africa.

The NGO Rural Advancement Foundation International (RAFI, Canada) identified 12 countries with VAD and a sufficient consumption of rice to make them a potential target for introducing Golden Rice. In six of these countries, no patents would hinder the production of Golden Rice; at least not until the Agreement on Trade-Related Aspects of Intellectual Property Rights (TRIPs) ends this IPR free situation.

ISAAA advised to negotiate for royalty-free licences from the patent owners, most of them being companies in the field of biotechnology. ISAAA suggested that in the current situation where these companies suffer from a bad image with consumers especially in Europe, licences would be easy to obtain. In contrast to other approaches like inventing around the existing patents or ignoring the patent claims, the obtaining of royalty free licences should ensure the possibility of future cooperation with patent holders.

Whether it might have been an option to concentrate on those countries with little or no patent conflicts and negotiate royalty-free licences for the rest, or whether the deal with Syngenta was the best option, time will tell. This example highlights the importance of knowledge about IPR issues in public research. It should worry everybody engaged in similar research for humanitarian projects that two notable universities in Switzerland and Germany apparently did not offer sufficient help to scientists on IPR issues.

The humanitarian project

[img_assist|nid=64|title=|desc=|link=none|align=right|width=107|height=138]As mentioned above, the exclusive rights of Golden Rice technology lie with Syngenta except its application for humanitarian uses. Syngenta itself will develop a product for the market in industrialized countries where vitamin A is considered as an agent against cancer and old age. The company intends to do the necessary product development and testing, and has announced that where appropriate it will make its data available to the humanitarian project.

The aim of the humanitarian project is to bring the GM trait of beta-carotene enhancement to those in need without a technology fee, but in practice suffering from VAD will not define the group of those in need. Instead, they are defined through their rice farming systems. Only farmers in developing countries who earn less than US$ 10,000 qualify for the humanitarian project. It is planned that the seeds will be distributed either directly through public institutions or via local breeders. As part of the programme, the farmers will own the seeds and will be allowed to re-sow from their harvest. There is no control system in place.

A Humanitarian Board, comprised of a number of public and private organizations like IRRI, The Rockefeller Foundation, The World Bank and Syngenta, is now giving the inventors of Golden Rice support in their work. This Board is chaired by Potrykus and includes his colleague, Beyer.

While those involved in the project praise it as a new form of private-public partnership in a humanitarian setting, critics consider it an inappropriate high-tech solution to the complex problem of food access, which has been taken up by life sciences companies and used for their own public relations. Ultimately, however, it will be governments, development organizations and local people who will have to make the choice about the measures they decide to adopt to combat malnutrition.