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Grand Challenges in Global Health Project
One of eight UN Millenium Development Goals is to reduce child mortality by two-thirds by the year 2015. More than 10 million children die every year unnecessarily, 90 percent of the casualties are concentrated in only 42 countries (Black et al. 2003). According to the World Health Organization (WHO), clinical to severe sub- clinical vitamin A deficiency (VAD) affects most developing countries. Simple measures, like breastfeeding, vitamin A and zinc supplementation could reduce the death toll by 25 percent. The combination of individual measures is capable of producing an effect that is greater than their sum (Jones et al. 2003).
In rice-based societies, daily food intake may comprise over 80 percent rice, as is the case in rural Bangladesh. Other components are vegetables (ca. 12 percent) and very little fish and other animal sources. In such countries, rice is also the main source of lipids and protein, even though milled rice contains only about 0.4 and 7 percent of these nutrients, respectively. This leads to a situation of well-fed people in terms of calories but malnourished in respect of a number of other essential nutrients.
Milled rice is poor in essential micronutrients. The problem with brown (unprocessed) rice—which contains some important micronutrients—is that it may not be stored for too long, because lipids contained in the outer layers undergo oxidation, rendering the grains rancid and unpleasant to the taste.
There is a clear association between VAD and a higher mortality rate among young children (Sommer and West Jr. 1996). The severity of VAD correlates with ocular signs, mainly xerophthalmia and its associated symptomatology, i.e. night blindness and corneal degeneration. About half of the children that become blind as a consequence of VAD die from various diseases, like measles or malaria, within a year of becoming blind.
Various intervention strategies have achieved notable results in a number of countries, yet even in the best cases approximately 30 percent of the population remains VA deficient. In average 55 percent of the children are covered by these interventions, but in countries like Peru, 90 percent of the children remain uncovered.
Typical interventions are education, industrial fortification, and supplementation. Industrial fortification, e.g. distribution of iodine-enriched salt or vitamin A-enriched margarine, is a common conduit to administer essential nutrients to an affluent population. Supplementation consists of providing children with one or two megadoses of vitamin A per year, usually as capsules. Serum retinol (vit A) levels drop significantly between interventions.
These interventions, currently being carried out by a numbers of national and international organizations, are limited by the logistic requirements of distribution networks—tens of thousands of helpers must be periodically mobilised—and the need for centralised processing. They are also affected by geographical limitations, making them only partially applicable. Even though the cost of the capsules and other supplements is very low, the cost of the campaigns, even for a small country the size of Nepal or Ghana, is in the range of US$ 2 million per year (MOST 2004). Furthermore, these campaigns do not reach children older than five nor pregnant or lactating women. These limitations make supplementation unsustainable in the long term.
Industrial fortification—which requires centralised processing—is hard to achieve in poor agricultural societies, where the produce of the land is consumed by the farmer and his family or traded locally. This sector of society is often served using the supplementation approach, i.e. by administration of capsules and the like. These programmes are usually linked to vaccination campaigns and other health-related services. Sadly, such campaigns usually do not attract mothers with children to the attention centres more than once a year. Urban areas are more accessible to supplementation programmes, but even though the share of urban population is constantly increasing all over the world, most countries with severe VAD are rural societies. Every affected country requires individually tailored programmes and relies mostly on foreign help and government goodwill. This explains why, according to UNICEF, in 1999 only 43 countries, out of 100 countries in need of supplementation, received 70 percent coverage of one yearly megadose to children under five years of age.
Biofortification represents a viable alternative for micronutrient delivery. This approach consists of plants producing or accumulating the desired nutrients in the edible parts. Traditionally, this is achieved by breeding (e.g. orange-fleshed sweetpotato), unless the desired trait is not available in existing, sexually compatible germplasm (as in rice). Biofortification offers a sustainable solution with the potential to complement current interventions and fill in existing coverage gaps left by supplementation programmes. The advantages of biofortification are evident: the generation of a plant variety is a one-off investment. In the case of genetic engi¬neering, the research phase can involve a high initial investment, justifiable by the expected socioeconomic impact. But once a trait has been engineered into a variety it can be easily transferred to any locally adapted variety by traditional breeding.
In poor, rice-based societies 3.8 million children die every year, that is 10,440 actual children deaths per day (Jones et al. 2003). People in such countries are the target population for programmes involving biofortified rice. Thanks to the Green Revolution of the 1960s, cereal production has been able to keep pace with population growth in developing countries, while other important crops, like pulses and vegetables, have lagged behind. Furthermore, the Green Revolution has brought prices for cereal crops down in the last 30 years, while prices for other food sources have increased. Biofortified cereals are thus again ideally suited for the task.
In the case of rice, biofortification is limited by the fact that there is no germplasm available among cultivated or wild relatives containing any provitamin A. A 1992 initiative by the Rockefeller Foundation led Prof Ingo Potrykus (ETH Zurich) and Prof Peter Beyer (University of Freiburg) to embark on the engineering of the provitamin A biosynthetic pathway in rice grains (Ye et al. 2000). At the end of an intensive basic research phase, a relatively simple genetic intervention provided a solution to a seemingly intractable problem. The result is now widely known as Golden Rice (GR). The only difference between GR and traditional rice is the carotenoid content and the pleasant golden colour of the grains.
All green plants synthesize carotenoids in leaves and very often in flowers. We obtain many of our dietary carotenoids from yellow fruits. In the rice grain, only two steps of a complex pathway leading to the production of carotenoids are interrupted. In GR the gap has been rebuilt by a genetic intervention involving the introduction of two genes, one of bacterial and another of plant origin. The bacterial gene from Erwinia uredovora is a carotene desaturase (CRT I), which catalyses the conversion of phytoene to lycopene. The gene of plant origin, originally from daffodil but isolated from maize in the newest constructs, is a phytoene synthase (PSY), which catalyses the conversion of geranygeranyl bisphosphate to phytoene (Paine et al. 2005; Schaub et al. 2005). These two steps at the entry point of carotenoid biosynthesis completely restore the pathway in the rice endosperm, leading to the preferential accumulation of beta-carotene (provitamin A).
It took five years from the breakthrough achievement of the first GR version to the first field trial! Contrary to what many external observers believed, putting the technology access agreements in place was the least of the problems. In exchange for rights to their invention, Beyer and Potrykus obtained access to a technology package owned by various companies, for humanitarian purposes. Smallholders in developing countries will have free access to GR technology with no strings attached, except for a yearly income cap of US$10,000, which is above the income level of smallholders in the target countries. So, why the delay? The major hurdle to progress of the GR Project remains regulatory in nature.
But the developers of GR have not rested on their laurels. Against the odds of destructive criticism by opponents of gene technology, GR has been further developed to accumulate enough beta-carotene to cover the recommended daily intake (RDI) in rice-based societies. The GR technology has been improved steadily, pushing the production and accumulation levels of beta-carotene higher and higher. To a great extent, progress has been possible thanks to the continuing support from Syngenta. The company has provided access to needed technologies and has also actively participated in producing regulatory clean lines and developed improved versions of GR (Paine et al. 2005). By exchanging the original daffodil PSY gene for a maize homolog, researcher at Syngenta were able to overcome the rate-limiting step of the reaction and thus obtain carotenoid levels 23x higher (and more) than in the first GR obtained in 1999. Lines with beta-carotene values between the first GR version and the new one had already been obtained by using endosperm-specific promoters and by selecting the best transformed lines. Remarkably, the overproduced carotenoids consist of more than 80 percent beta-carotene (provitamin A).
An international network, consisting of national agricultural research institutions, has been set up in target countries to guarantee outreach of the GR Project to the malnourished poor in those countries. Every institution in this so-called Golden Rice Network is involved in breeding of locally adapted GR varieties and making sure that planting material reaches the farmers. This is achieved by introgression of the beta-carotene production trait from a regulatory clean variety into local varieties, a process that may take around two years to complete.
The first GR field trial took place in the USA, because it was the only country that had in place pragmatic, science-based biosafety regulations. Permits for trials in India and the Philippines were not signed off in time for the rice-growing season. Various versions of GR are now finally growing in greenhouses in the Philippines, India, and Vietnam. The first field trials in Asia will take place later this year. In the meantime, two trials have already taken place in the US, whereby no agronomic problems were detected and the level of provitamin A in the grain was higher than that obtained in the greenhouse by the same lines.
The field trials with GR and the arrival of selected GR lines in Asia for introgression are recent major breakthroughs of the GR Programme. Approval will be sought on a country-by-country basis and will involve the completion of regulatory dossiers as required by national laws. It is hoped that most information contained in the regulatory dossier will be transferable from country to country, eg using the Biosafety Clearinghouse mechanism established by the Convention of Biological Diversity (CBD).
A number of factors affect the intestine’s ability for provitamin A uptake from different foodstuffs. Carotenoids are often tightly bound to sub-cellular structures, thus a certain level of cooking usually enhances extractability; carotenoids are quite heat stable. In some foodstuffs carotenoids form insoluble crystals, as in carrots, thus high content is not necessarily a measure for nutrient supply. Further food processing takes place in the mouth and in the intestine, where the presence of fat in the diet increases uptake. The starchy rice endosperm is a simple food matrix, which also includes lipid membranes. Thus, bioavailability of carotenoids in GR is expected to be high.
While earlier versions of GR would have been able to provide only 50 percent RDI in conjunction with existing diets, a conservative calculation predicts that the latest GR version will be able to provide more than 100 percent RDI to people living in rice-based societies.
The last remaining hurdle before release of GR to smallholders is obtaining regulatory approval. A problem with present regulatory regimes is that they have made the approval of transgenic crops prohibitively expensive. Publicly funded projects are not in a position to bear those costs. Overly complex regulatory frameworks have been set up in many countries, supposedly to protect consumers. Extensive evidence from widespread production and consumption of GM plants indicates that no specific harm emanates from transgenic crops, while very clear life-threatening conditions arise from the lack of micronutrients.
The regulatory equation blows up the theoretical risk and ignores the real benefit. According to a World Bank analysis, gains from improved health will by far surpass farming gains, amounting to billions of dollars. Expected losses stemming from European import bans would amount to less than 0.5 percent of the projected gains (Anderson et al. 2004).
Hunger and malnutrition affect all developing countries. Providing a solution to VAD only addresses part of the problem. Multiple nutrient deficiencies, including lack of iron, zinc, iodine, and high-quality protein lead to a serious, worldwide problem. Therefore, we have now embarked in a multi-pronged approach to tackle this compound problem in a concerted fashion by making GR more micronutrient dense. A main objective of the new project is to generate rice lines harbouring multiple traits in a single genetic locus, to facilitate breeding into local cultivars.
Biofortification is progressing at multiple levels: multi-institutional, multicrop, multitrait, multistrategy, transgenic and non-transgenic. This task is being pursued by the ProVitaMinRice Consortium, led by the group of Peter Beyer of the University of Freiburg. The Consortium further includes groups from Michigan State University, Baylor College of Medicine (Houston, Texas), the International Rice Research Institute and PhilRice, in the Philippines, the Cuu Long Delta Rice Research Institute, in Vietnam, and the Chinese University of Hong Kong. Three other projects funded through the Grand Challenges in Global Health Initiative of the Bill & Melinda Gates Foundation are following the lead of the GR technology. These projects are applying similar approaches to cassava, banana, and sorghum. Their common goal is to stack multiple traits together: carotenoid production, iron and zinc accumulation, vitamin E and high-quality protein production.
In sum, biofortification combining genetic engineering and traditional breeding offers a sustainable, non-intrusive solution to a life-threatening problem that affects millions of poor people, especially children, around the world.
Bibliography- Anderson K, Jackson LA, Pohl Nielsen C (2004) Genetically modified rice adoption: Implications for welfare and poverty alleviation. Centre for International Economic Studies. Discussion Paper No 0413.
- Black RE, Morris SS, Bryce J (2003) Where and why are 10 million children dying every year? Lancet 361:2226-2234. Jones G, Steketee RW, Black RE, Bhutta ZA, Morris SS, and the Bellagio Child Survival Group (2003) How many child deaths can we prevent this year? Lancet 362:65-71.
- MOST, USAID Micronutrient Program (2004) Cost analysis of the national vitamin A supplementation programs in Ghana, Nepal, and Zambia: A synthesis of three studies.
- Paine JA, Shipton CA, Chaggar S, Howells RM, Kennedy MJ, Vernon G, Wright SY, Hinchliffe E, Adams JL, Silverstone AL, Drake R (2005) Improving the nutritional value of Golden Rice through increased pro-vitamin A content. Nature Biotechnol, 23:482-487.
- Schaub P, Al-Babili S, Drake R, Beyer P (2005) Why is Golden Rice golden (Yellow) instead of red? Plant Physiol 138:441-450.
- Sommer A, West Jr. KP (1996) Vitamin A deficiency: Health, survival and vision. Oxford University Press.
- Ye X, Al-Babili S, Klöti A, Zhang J, Lucca P, Beyer P, Potrykus I (2000) Engineering the Provitamin A (beta-carotene) biosynthetic pathway into (carotenoid-free) rice endosperm. Science 287:303-305.
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