Electronic Journal of Biotechnology

Micronutrient malnutrition is the source of severe medical problems in developing countries. Of the 24'000 deaths per day attributed to this problem, probably 6'000 are due to vitamin A malnutrition. Traditional interventions do not reach the majority of the needy and, therefore, alternative interventions are required. Biofortification – improvement of the micronutrient content of crops on a genetic basis - has been recognized as a cost-effective, sustainable, complementary intervention. Golden Rice represents the first case of GM-based biofortification. In Golden Rice genes have been introduced to activate the biochemical pathway leading to the synthesis and accumulation of carotenoids (pro-vitamin A) in the rice endosperm, the edible part of the rice seed. Scientific proof-of-concept was completed in spring 1999 (Ye et al. 2000). The motivation for this ‘scientific tour de force' was from the onset a humanitarian one: to contribute to a reduction in vitamin A malnutrition in developing countries. The scientists involved did not expect that transferring the benefits of the scientific breakthrough to the needy would constitute such a complex and time-consuming task. And in view of the problem it is difficult to accept that it is taking at least ten years, to deliver a deregulated product.

Golden Rice was moved into the political limelight as an example of what benefits consumers could expect from the new technology, but also as the favourite target of the GMO-opposition, which was disturbed by the positive response, and which fought the case for its potential as a “Troyan horse”, opening the ground for acceptance of the technology. Their claim that Golden Rice was ‘Fools' Gold' because children would have to eat up to 9 kg per day became a politically very effective counter-strategy. Although this claim was never true, it had a pronounced negative effect on the media, the public, and governmental agencies. Meanwhile, lines have been developed and are available to the Humanitarian project, where ca. 70g per day would provide the recommended daily allowance of vitamin A (Paine et al. 2005).

The above calculation is based on a 16 mg/g line, but lines with more than 32 mg/g are now available. With these lines the GMO opposition has definitely lost its last argument against Golden Rice and, hopefully, will finally accept that GMO technology can be used to the benefit of the poor. For its potential, Golden Rice should be made available to the poor as fast as possible, but under the present regulatory regime this is a very time-consuming and expensive task. The inventors of Golden Rice realized soon that the public domain was not in the position to carry Golden Rice successfully through the process of product development and deregulation, and it was a fortunate coincidence that the private sector, the companies Zeneca and subsequently Syngenta, were ready to support the humanitarian project in exchange for commercial rights in the invention. This ‘Public-Private-Partnership' was instrumental for the entire further process, including organization of free licences for involved intellectual property rights. Over the years, it became more and more obvious that under the present regulatory regimes, public humanitarian projects, such as Golden Rice, will fail if not supported by the private sector. The public sector has little expertise and experience in and no financial resources for product development; but the almost insurmountable hurdle is the extremely complex, time-consuming, and expensive process of deregulation, which has ‘evolved' to such a level, that only large and financially strong companies can cope with it. The effect is that public R&D can at best compete in basic research, but is cut off from product development and release of public GMOs into the marketplace. This is a very serious consequence, because it affects virtually all possible public contributions to solutions of humanitarian problems. And it is the public domain which is responsible for solving humanitarian problems. This responsibility can not be delegated to the private sector, which is dependent upon commercial success. The progress achieved with the humanitarian Golden Rice project was possible only because a successful Public-Private-Partnership could be established between the inventors of the Golden Rice technology and the Syngenta company.

The great advantage of GMO seeds is the fact that the entire technology is embedded in the seed. Looking at the potential of one Golden Rice seed, we realize that each seed can produce 20'000 metric tons of Golden Rice within two years (1 seed grows into a plant with 1'000 seeds or 20 g; the next generation will arrive at 20 kg; the next at 20 t and the next at 20'000). 20'000 t of rice are sufficient to feed 100'000 people for one year which, if in the case of Golden Rice will also protect them from vitamin A deficiency. All a farmer needs to benefit from this technology is one seed. He needs no additional agrochemicals or pesticides nor novel farming systems. He may use part of his harvest for the next sowing. No new dependencies are created. Furthermore, the technology is free up to a yearly income of USD 10'000 per farmer or local trader per year. World Bank Policy Research Working Paper no. 3380, from August 2004 carrying the title ‘Genetically Modified Rice Adoption: Impact for Welfare and Poverty Alleviation' by K Anderson, LA Jackson, and CP Nielson concludes that impressive benefits might be accrue for countries adopting the technology. The paper uses the ‘global economy-wide computable general equilibrium model' to analyse the potential economic effects of adopting first and second generation GMO crops in Asia. Two citations from the abstract: ‘The results suggest that farm productivity gains could be dwarfed by the welfare gains resulting from the potential health-enhancing attributes of Golden Rice.' ‘Projected gains from Golden Rice adoption by developing Asia would amount to USD 15.2 billion.' But extreme precautionary regulation, so far, prevents use of the technology.

‘Extreme precautionary regulation' has been adopted world wide and is, to date, widely accepted, and international organizations are helping to introduce it into numerous developing countries. In the context of the Humanitarian Golden Rice project the experience is that this approach delays product development and deregulation by at least six years, and consequently the question should be asked: “Is GMO over-regulation costing lives?” The following, straightforward calculation arrives at a shocking answer: If Golden Rice would not have been a GMO (which is not possible, because production of provitamin A in rice endosperm is only possible via genetic engineering), breeders would have able to develop varieties by 2002 (e.g. seven backcrossing generations into IR64) and farmers could have started using Golden Rice from 2003 on. Because of GMO regulation Golden Rice will not reach the farmer before 2009 – with at least 6 years of delay. Every day 6'000 children die from vitamin A deficiency; probably half of those (3'000) from rice-dependent vitamin A deficiency. Assuming only a 1 percent Golden Rice adoption (far higher values are probably more realistic), 65'700 GMO regulation caused deaths could be prevented (30X365X6). How can our society tolerate 65'700 avoidable deaths, by supporting an ‘extreme precautionary regulation' approach?

We have GMO regulations for historic reasons: At the beginning of GMO technology development the scientists themselves established regulations and it was sensible to be ‘precautious' during the early phases of technology development. The main argument was, and still is, that the technology could lead to unpredictable and uncontrolled alterations in the genome of the experimental organism. This was and still is true. However, experience from more than 20 years of deregulation, from thousands of ‘biosafety' experiments and from experiments performed to satisfy the requirements of hundreds of dossiers for deregulation, from release of GM plants into the environment on over 90 million hectares, and from deliberations of several academies and numerous publications we know nowadays that there is no technology-specific risk which did not exist before as the consequence of traditional plant breeding, and for which we have ample of experience to control it, if necessary. Why then do we maintain ‘extreme precautionary regulation'? The argument is, that this regulation is mandatory to build trust for acceptance by consumers. Experience has widely demonstrated that this does not work, and that is not surprising: How can an unbiased citizen trust a technology which is so tightly regulated. If something is regulated in the way that GMOs are, the conclusion is that it must be dangerous! And how do we continue to justify ‘extreme precautionary regulation'? It is stated that it can not be excluded with 100 percent certainty that unintended alterations of the genome may have adverse effects which may even show up only in evolutionary time scales (how is it possible to relate this argument of an imaginary, potential adverse effect on an evolutionary time scale with the 65'700 regulation-caused deaths!). Above all, this argument applies to all our crop plants, which have been developed using traditional plant breeding techniques, and which we have been consuming for ages without any regulation – and without ‘adverse effects'. So, where is the argument which justifies maintenance of ‘extreme precautionary regulation'?

Traditional breeding, from which we all depend, is causing loads of ‘unpredictable and uncontrollable genome alterations'. It uses ‘landraces' (the yellow arrowheads) which differ from each other by (random and totally undefined) ‘mutations' (yellow bars). The landraces are crossed with each other and subsequently selected for novel varieties (the blue squares with @) and). This process induces ‘recombinations' (pink bars), ‘translocations'(blue bars), ‘inversions'(orange bars), ‘deletions' (white bars), and is also accompanied by ‘transpositions' of mobile genetic elements. Each of these breeding steps is loaded with dramatic ‘unpredictable' genome alterations, and the ancestry of modern crop varieties includes many such steps along which all such genome alterations occur and accumulate. The graph below depicts the ‘breeding tree' (the history) of the Indica rice variety IR64, the most popular and successful rice variety world-wide. All crop varieties in use have similar histories. Therefore, all our present-day varieties, including those used by organic farmers, are thoroughly ‘genetically modified'. We consume nothing but food from ‘genetically modified organisms'. And our experience is that nobody has been harmed by eating them – without any GMO regulation.

The difference between our ‚genetically modified' traditional crop varieties and the novel‚ genetically engineered'crop varieties, which are so over-regulated that they can not be further developed and used by the public domain, is a relatively minute, precisely studied, and highly predictable recombination step, and by far less ‘uncontrolled and unpredictable' than anything else done in traditional breeding. The ‘blue box' represents graphically the plant genome as a result from evolution before early farmers began to use spontaneous alterations. The yellow bars show mutations, recombinations pink, translocations blue, transpositions black, inversions green, and deletions white, as mentioned earlier, all unpredictable and uncontrolled genome alterations.

The author does not understand, why a precise ‘genetic engineering' step, despite all our present knowledge, must be so heavily regulated, while traditional genetic modifications, being by far heavier and more extensive, are accepted without any regulation. The only argument put forward is, that we have the experience that it does no harm to eat them. Well, we have the same experience for GMOs and there is no reason (see above) to handle them differently.

Present regulations require a thorough safety assessment (for GMOs only) which includes a detailed description of the genetic modification (methods used, function and regulation of the gene(s), characterization of the gene in the modified organism, stability of the genetic changes), general safety issues (history of use, nature of new protein, impact from potential transfer into cells of the human digestive tract), toxicological issues (levels of naturally occurring toxins, potential toxicity of new protein, potential allergenicity of new proteins, level of naturally occurring allergenic proteins), nutritional issues (nutrient analysis, levels of anti-nutrients, ability to support typical growth and well being).

Intensive experimental investment of an entire team for nearly a decade is needed to fulfil all requirements for successful deregulation of a single transgenic event. This is something no public institution around the world, not even in the richest industrialized countries, can afford. ‘Regulatory clean' events are required to have a fair chance to pass through the deregulatory process, i.e. events which have passed the rigid regulatory molecular analysis requirements. All experiments must be done with ‘regulatory clean constructs' and ‘regulatory clean technology' to have a chance to arrive at such a ‘regulatory clean event'. And finally, to find a ‘regulatory clean event with stable and high levels of expression' of the desired gene, years of repetition of the same experiment must be wasted. All this is far beyond the financial and mental capacity of any public laboratory, where scientists can survive the competition only, if they publish (nothing of what has been described above can be published) and where grants are provided for scientific novelty (nothing of the above leads to scientific novelty). Once a ‘regulatory clean event with high and stable expression of the gene' has been identified, work for variety development can begin, and in parallel with that, and finally with the final product, the work for the regulatory dossier can be carried out. Again, this is work for many years, with no opportunity for publication or financial support. Therefore, the consequences of ‘extreme precautionary regulation' are that the public domain, which has the obligation to use the technology for the solution of humanitarian (or public) problems, can not do so. And powerful industries, which would have the potential to use the technology for product development, have to focus on projects with a substantial financial return, and can thus at best make minor investments to support public projects. This unhealthy situation would change immediately to the better as soon as ‘extreme precautionary regulation' was replaced by science-based ‘rational regulation'.

There are just a few questions and answers which should satisfy the understandable desire for food and environmental safety. To illustrate the case I am using the example of Golden Rice:

Q:        What is novel?
A:        Carotenes in the endosperm.
Q:        Any possible negative effects on the environment?
A:        No, because no biological basis for any selective advantage.
           Therefore: No restriction for experimental growth in the field. (In reality we are still waiting for permission for the first field testing in developing countries!).
Q:        Any possible positive effects for the consumer?
A:        Yes: Potential for cost-effective, sustained reduction of vitamin A deficiency.
Q:        Any possible negative effects for the consumer?
A:        No, because of activation of the natural pathway with not a single novel product.

Therefore: Immediate and unrestricted development and registration of locally adapted varieties.(In reality product development and deregulation is so difficult, that the use of the technology is delayed for at least 6 years, not to mention the extremely high costs involved.)

Golden Rice is only one of numerous examples for the use of GM technology in the public domain for humanitarian applications, and we have shown above, that the delayed use of Golden Rice costs at least 65'700 lives. There are hundreds of further ‘food-security' transformation events produced in the public domain in Egypt, Kenya, South Africa, Zimbabwe, China, India, Indonesia, Malaysia, Pakistan, Philippines, Thailand, Argentina, Brazil, Costa Rica, Mexico, etc., established in maize, pearl millet, sorghum, wheat, potatoes, cassava, sweet potatoes, melons, cucumbers, squash, watermelons, tomatoes, bananas, plantain, beans, papaya, sunflower, soybean, ground nut, chickpea, oil palm, cabbage, cauliflower, cacao, mango etc, with improved agronomic performance, stress tolerance, and nutritional value (Cohen, 2005). All these cases will face the same prohibitory regulation regime as discussed above. Therefore, GMO regulation-caused death will expand into the hundreds of thousands.

Science and GMO technology are meanwhile moving towards ‘nutritional optimization' via biofortification. Golden Rice will contribute to a solution of vitamin A malnutrition in rice-based societies. Within the next five years we will see ‘Golden Sorghum', ‘Golden Cassava', ‘Golden Banana' to extend the administration of provitamin A to populations depending on these crops. However, micronutrient malnutrition is often a problem of multiple, complex deficiencies, including iron, zinc, high quality protein, other vitamins, etc. Thanks to a generous grant from the Melinda and Bill Gates Foundation to the NIH Foundation, international teams have been established and work has begun within the framework of the ‘Grand Challenges in Global Health' initiative to develop high vitamin A, high iron, high zinc, high essential amino acid rice, sorghum, cassava, and banana. If scientifically successful, this approach will provide nutritional optimised crops with the potential to reduce the complex micronutrient deficiencies responsible for the 24'000 daily deaths. Again, each single trait will face the same problems as discussed with Golden Rice, but multiple-trait transgenics will not even have a chance to be deregulated at all. Therefore, the number of GMO-regulation-caused deaths will expand into many millions. Millions of avoidable deaths should be considered ‘a crime to humanity'. Extreme precautionary regulation can be accused of this crime. Who will take responsibility for ‘extreme precautionary regulation'?

Golden Rice will be available at no cost within the framework of a Humanitarian Golden Rice project. For more details please visit the www.goldenrice.org website. Golden Rice has not been deregulated yet, but there is no conceivable scientific argument to assume any threat to the consumer or the environment (see also discussion above on ‘rational regulation').

Less than 100 g of Golden Rice per day will be sufficient to supply the required dose of vitamin A to live a healthy live. Golden Rice can, therefore, substantially reduce vitamin A malnutrition in rice-based societies in a cost-effective, sustainable manner.

Partner institutions in India, China, Vietnam, The Philippines, and Bangladesh are transferring the novel trait into carefully selected national rice varieties.

The Humanitarian Golden Rice Board is taking every possible effort to help in the preparation of a dossier for deregulation, but it is not in the financial position to carry national varieties through the deregulation process.

It will be up to the national governments to take up this challenge, hopefully saving time and costs by applying ‘rational' instead of ‘extreme precautionary' regulation.

The humanitarian project would have never reached the present state without the continuous support from Syngenta (especially Dr. Adrian Dubock), the financial support from he Rockefeller Foundation, Syngenta Foundation for Sustainable Agriculture, and USAID, and in-kind support from all licensees and individuals from the Humanitarian Board and Network, the University of Freiburg, USAID, IFPRI, Syngenta, SDC, IRRI, USDA, the Rockefeller Foundation, Bayer, Japan Tobacco, Monsanto, Mogen, Novartis, Zeneca. Special acknowledgements deserve Prof. Peter Beyer (the co-inventor of the Golden Rice technology) and his team as well as the Syngenta team behind the recent publication for continuous improvement of the underlying science.

YE, Xudong; AL-BABILI, Salim; KLÖTI, Andreas; ZHANG, Jing; LUCCA, Paola; BEYER, Peter and POTRYKUS, Ingo. Engineering the provitamin A (b-Carotene) biosynthetic pathway into (carotenoid-free) rice endosperm. Science, January 2000, vol. 287, no. 5451, p. 303-305. [CrossRef]

PAINE, Jacqueline A.; SHIPTON, Catherine A.; CHAGGAR, Sunandha; HOWELLS, Rhian M.; KENNEDY, Mike J.; VERNON, Gareth; WRIGHT, Susan Y.; HINCHLIFFE, Edward; ADAMS, Jessica L.; SILVERSTONE, Aron and DRAKE, Rachel. Improving the nutritional value of Golden Rice through increased pro-vitamin A content. Nature Biotechnology, April 2005, vol. 23, no. 4, p. 482-487. [CrossRef]

SCHAUB, Patrick; AL-BABILI, Salim; DRAKE, Rachel and BEYER, Peter. Why Is Golden Rice Golden (Yellow) Instead of Red? Plant Physiology, 2005, vol. 138, no. 1, p. 441-450. [CrossRef]

COHEN, Joel I. Poorer Nations turn to publicly developed GMO crops. Nature Biotechnology, January 2005, vol. 23, no. 1, p. 27-33. [CrossRef]

Important websites:

Ingo Potrykus
Professor Emeritus Plant Sciences
Swiss Federal Institute of Technology (ETH) and Chairman of the Humanitarian Golden
Rice Board & Network
Switzerland
ingo@potrykus.ch
www.goldenrice.org