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Experience from the Humanitarian Golden Rice Project: Extreme Precautionary
Regulation Prevents Use of Green Biotechnology in Public Projects

BioVision Alexandria 3-6 April 2004
Ingo Potrykus
Professor emeritus Plant Sciences, ETH Zuerich, Switzerland

Biofortification can complement traditional interventions against malnutrition.

In developing countries 500,000 per year become blind and up to 6,000 per day die from vitamin A-malnutrition. And this is despite enormous efforts from public and philanthropic institutions to reduce this medical problem with the help of traditional interventions such as supplementation, fortification, encouragement for diet diversification, etc. This heavy toll poor people in developing countries are paying to vitamin A-malnutrition will continue year by year, if we do not find a way to complement traditional interventions by sustainable and unconventional ones. One of those could be based on nutritional improvement of basic staple crops via "bio-fortification" - genetic improvement with regards to micronutrients and vitamins. Plant breeding and genetic engineering offer two complementing approaches.

The major micronutrient deficiencies concern iron, zinc, and vitamin A. Vitamin A-deficiency is wide-spread amongst rice-depending poor because rice does not contain any pro-vitamin A (Plants do not produce vitamin A but pro-vitamin A (carotenoids), which our body converts into vitamin A) . Dependence on rice as the predominant food source, therefore, necessarily leads to vitamin A-deficiency if poverty prevents a diversified diet, most severely affecting children and pregnant women. The medical consequences for the vitamin A-deficient 400 million rice-consuming poor are severe: impaired vision - in the extreme case irreversible blindness - impaired epithelial integrity against infections, reduced immune response, heamopoieses, skelettal growth, etc. Rice containing pro-vitamin A could substantially reduce the problem, but "bio-fortification" of rice for pro-vitamin A is not possible without genetic engineering. The transgenic concept, therefore, was based on the idea to introduce all genes necessary to activate the biochemical pathway leading to synthesis and accumulation of pro-vitamin A in the endosperm (the starch storage tissue of the seed).

The scientific breakthrough with pro-vitamin A.

"Golden Rice" contains the genes necessary to activate the biochemical pathway for pro-vitamin A. This pathway is activated exclusively in the endosperm. The intensity of the "golden colour" represents the concentration of pro-vitamin A. There are different lines with different concentrations. We aim at concentrations, where a daily diet of 200g of rice will provide enough pro-vitamin A to substantially reduce vitamin A deficiency. The concentration required for this purpose can only be determined, when data from bio-availability studies are available. Experiments on these lines are in progress, but will take until end of 2005. So far we are working with lines in which -theoretically - the concentration is high enough for our goal.

The novel trait has been transferred into several Indica rice varieties - especially IR 64, the most popular rice variety of Southeast Asia, and "regulatory clean" events have been selected to facilitate the processing through the deregulatory process. (Ye, X., Al-Babili, S., Klöti, A., Zhang, J., Lucca, P., Beyer, P., Potrykus, I. (2000). Engineering provitamin A ( -carotene) biosynthetic pathway into (carotenoid-free) rice endosperm. Science 287, 303-305. Beyer P, Al-Babili S, Ye X, Lucca P, Schaub P, Welsch R, Potrykus I (2002) Golden Rice: introducing the -carotene biosynthetic pathway into rice endosperm by genetic engineering to defeat vitamin A deficiency. J Nutrition 132: 506S-510S. Tran Thi Cuc Hoa, Salim AlBabili, Patrick Schaub, Ingo Potrykus, and Peter Beyer (2003). Golden Indica and Japonica rice lines amenable to deregulation. Plant Physiology 133, 161-169.)

Golden Rice will be made freely available in a humanitarian project.

Golden Rice will be made available to developing countries in the framework of a "Humanitarian Golden Rice Project". This was from the beginning a public research project, designed to reduce malnutrition in developing countries. Thanks to strong support from the private sector and donations of "free licences for humanitarian use" for intellectual property rights involved in the basic technology, the hurdle of extended IPR linked to the technology used in the scientific project could be overcome. This enables us to collaborate with public rice research institutions in developing countries on the basis of "freedom-to-operate" towards the development of locally adapted Golden Rice varieties. Once Golden Rice varieties have passed the national bio-safety procedures, it will be made available to subsistence farmers free of charge and limitations. It will become their property and they can - year after year - use part of their harvest for the next sowing (without paying anything to anybody). The farmers will use their traditional farming systems and they will not require any additional agronomic inputs. Therefore, there will be no "new dependencies" from anyone. And there is no conceivable risk to any environment which would justify not to grow Golden Rice in the field for breeding and up-scaling reasons. This progress since the scientific breakthrough in 1999 was possible thanks to a novel type of "public-private-partnership". Thanks to an agreement with Syngenta and other agbiotech industries, the use of Golden Rice is free of licenses for "humanitarian use", defined as "income from Golden Rice per year and farmer below $ 10'000.-. "Commercial use", however, (above $ 10'000.- per year) requires a license from Syngenta. Humanitarian use is based on (license-free) sublicenses from the Humanitarian Golden Rice Board (contact: Professor Ingo Potrykus) to public rice research institutions. This sublicense agreement ensures that the material is handled according to established GMO rules and regulations, and that the target population - subsistence farmer and urban poor -receive the material without any additional cost for the trait.

Locally adapted varieties are being developed in national institutions in the framework of a Humanitarian Golden Rice Network under the guidance of a Humanitarian Golden Rice Board.

Development of locally adapted Golden Rice varieties as well as application to national bio-regulatory authorities for field testing and deregulation is in the hands of national and international public rice research institutions. To date this "Humanitarian Golden Rice Network" includes 16 such institutions in Bangladesh, China, India, Indonesia, South Africa, The Philippines, and Vietnam. The network is under the strategic guidance of the Humanitarian Golden Rice Board, and under the management of a network coordinator with office at the International Rice Research Institute (IRRI), Philippines. The Humanitarian Board has, so far, no legal status and benefits from the expertise of international authorities such as Dr. Gurdev Khush, retired from IRRI (rice breeding), Prof. Robert Russell, Laboratory for Human Nutrition, Tufts University Boston (vitamin A-malnutrition), Dr. Howarth Bouis, International Food Policy Research Institute (IFPRI) Washington (bio-fortification), Dr. Gary Toenniessen, The Rockefeller Foundation New York (food security in developing countries), Dr. Robert Bertram, USAid Washington (development in Third World agriculture), Dr. Adrian Dubock, Syngenta (product development and intellectual property rights), Dr. Ren Wang / Dr. William Padolina IRRI (international cooperation in rice research), Professor Peter Beyer (co-inventor) university of Freiburg (scientific progress underlying bio-fortification in pro-vitamin A and other micronutrients), Dr. Katharina Jenny, Swiss Development Cooperation Bern (technology transfer and trans-sectorial issues), and Professor Ingo Potrykus (co-inventor), retired from ETH Zuerich, chairman (public relations and information).

Biofortified seeds have an unmet potential for sustained solutions.

Bio-fortification (complementation for missing micro-nutrients with the help of genetic complementation) of the basic staple crops for poor populations in developing countries is, most probably, the most sustainable and cost-effective approach to reduction in micro-nutrient malnutrition. (For more information on the concept of bio-fortification and a recent challenge program of the CGIAR see homepage www.harvestplus.org). Golden Rice represents the first example of bio-fortification achieved via genetic engineering. Research investment for this trait (bio-fortification for pro-vitamin A) was relatively modest ($ 2,4 million over 9 years) and financed from funds for basic research.

Product development, however, from this scientific brake-through is time consuming and requires additional funding, but again one-time only for each event. Expenses are increasing really dramatically when working through the bio-safety assessments required for deregulation. But again this is a one-time investment. As soon as a novel bio-fortified variety is deregulated and can be handed out to the farmer, the system demonstrates its unique potential, because from this point on, the technology is built into each and every seed and does not require any additional investment, for an unlimited period of time. Just consider the potential of a single Golden Rice seed: Put into soil it will grow to a plant which produces, at least, 1 000 seeds; a repitition will yield at least 1 000 000 seeds; next generation produces already 1 000 000 000 seeds and in the fourth generation we arrive at 1 000 000 000 000 seeds. These are 20 000 metric tons of rice and it takes only two years to produce them. From these 20 000 tons of rice 100' 000 poor can survive for one year, and if they use Golden Rice they have an automatic vitamin A supplementation reducing their vitamin A-malnutrition, and this protection is cost-free and sustainable. All a farmer needs to benefit from the technology is one seed! There is no additional input required compared to "normal rice". And for urban poor there is no premium on vitamin A-rice. There are enough seeds to be handed out to many farmers, but this can not be done, because Golden Rice is a "GMO" (genetically modified organism) and those are highly regulated. And the Humanitarian Golden Rice Board has decided to follow the established rules and regulations.

Extreme precautionary regulation, however, prevents use so far and ignores the potential benefits.

Considering the history of Golden Rice (the technology is often considered risky because it is so fast!) it took 10 years (from 1980 to 1990) to develop the necessary technology of placing genes into rice. It took further 9 years (from 1990 to 1999) to introduce the genes required to establish the biochemical pathway leading to pro-vitamin A in the seed. And it took further 5 years (from 1999 to 2004) to develop a Golden Rice "product" and carry it across a series of GMO-specific hurdles such as IPRs. And it will take, probably, at least 5 more years to advance the first Golden Rice product through the deregulatory procedure: Therefore, it took 30 years if we include technology development, and it took still 20 years for the single specific case. Considering that Golden Rice could substantially reduce blindness (500 000 per year) and death (2-3 million per year) 20 years are a very long time period, and I do not think that anyone should complain that this was "to fast"! If it were possible to shorten the time from science to the deregulated product, we could prevent blindness for hundreds of thousands of children! However, the next 5 years will have to be spent on the required "bio-safety assessments" to guarantee that there is no putative harm from Golden Rice for the environment and the consumer. Nothing speaks against a cautious approach, but present regulatory praxis follows an extreme interpretation of the "precautionary principle" with the understanding that not even the slightest hypothetical risks can be accepted or left untested, and at the same time all putative benefits are totally ignored. Looking at Golden Rice and the problem of environmental risk assessment discloses how irrational the present system operates : The author has, over the last four years, not found any ecologist, including those from the "professional GMO-opposition", who could construct a half-way realistic hypothetical risk from Golden Rice to any agronomic or wild environment. This is not surprising because the entire biology of the system - low amounts of additional -carotene in the endosperm in plants which are loaded with -carotene in every organ except for the root - does not provide for any selective advantage in any environment, and therefore can not pose any substantial risk. Despite this fact Golden Rice is still awaiting the first permission for the first small-scale field release, in which environmental risks have to be studied experimentally! So far to the "risk" side of the equation. And the "benefit"? Golden Rice could prevent blindness and death of hundreds of thousands of children but can not do so, so far, because risk assessment notoriously is ignoring a risk-benefit analysis!

Present Deregulation is extremely demanding on time and financial resources

What then is required for the deregulatory procedure? First of all, it is advisable to focus on one carefully selected transgenic event, which is as "regulatory clean" as possible - that is, it must not include characters which are a priori unpopular with regulatory authorities, such as "multiple integrations", "rearrangements", "read-through across T-DNA borders", "microbial origins of replication", "ballast DNA", etc. This requires the production of many hundreds of similar transgenic events with the same DNA construct. This construct itself must have been assembled taking into account the requirements of the regulatory authorities in the later deregulation process. Only when working on the basis of a "regulatory clean construct" and with "regulatory clean transformation technology" there is a chance to survive the deregulation. Such a carefully selected event can then be used to start the series of bio-safety assessment experiments traditionally expected to prove or disprove any putative bio-safety hazard. (It is a waste of time to enter the process with material which is not "regulatory clean" at the onset). The consequence of this approach is, that nearly 99% of transgenic events, and often those with the highest levels of expression, have to be discarded. Already this first step of mass production of many hundreds of similar events and subsequent destruction of most is beyond the scope of any public research institution, not only in developing but also in developed countries. No funding agency would be willing to finance this step. This is, however, the first prerequisite for entering the deregulation procedure with some chance for success.

Once the right material is ready, bio-safety assessment can start. There are "event-independent" studies which refer to the introduced genes and their function in general, and which are valid for all events produced with these genes. "Exposure evaluation" (for the novel trait, e.g. pro-vitamin A in rice) studies the intended use and bio-availability. This study alone takes about 3 years, because the material has to be produced in specific plant growth chambers due to the lack of permission for field release (see above!). "Protein production and equivalence" analyses the proteins through which the genes fulfil their function. For this purpose the proteins have to be isolated from the plant, biochemically characterized, and their function confirmed. Lack of homology to toxins and allergens, rapid degradation in gastric/intestinal studies, heat lability, acute toxicity in rodent feeding, screening for further putative allergens and toxins are assumed to ensure that no unintended toxin or allergen will be consumed with Golden Rice. This seems reasonable if we ignore that most people have eaten these genes and gene-products throughout his/her life from other food sources. To study, as has been proposed, whether Daffodil toxins have been introduced into Golden Rice (one gene is from Daffodil and it is not advisable to consume Daffodil ) demonstrates how far an assessment can be from science: what has been transferred is one defined piece of DNA with no relation whatsoever to any toxin or allergen!). These studies take at least 2 years of intensive work in a well equipped biochemistry laboratory. What has been described, so far, was only an introduction; the real work comes with the "event-dependent" studies: "Molecular characterization and genetic stability" (single copy effect; marker gene at same locus; simple integration; Mendelian inheritance over at least three generations; no potential gene disruption; no unknown open reading frames; no DNA transfer beyond borders; no antibiotic resistance gene or origin of replication; insert limited to the minimum necessary; insert plus flanking regions sequenced; phenotypic evidence and biochemical evidence for stability over three generations). "Expression profiling" (Gene expression levels at key growth stages; evidence for seed-specific expression); "Phenotype analysis" (Field performance, typical agronomic traits, yield compared to isogenic lines; pest and disease status same as origin). "Compositional analysis" (Data from two seasons times six locations times three replications on proximates, macro- and micro-nutrients, anti-nutrients, toxins, allergens; data generated on modified and isogenic background). "Environmental risk assessment". This requires 4-5 years of an entire research team.

No public scientist or institution can afford such a deregulation procedure.

It is rather obvious, that no scientist nor scientific institution in the public domain has the potential, or funding, or motivation to perform such bio-safety experiments. It is, therefore, no surprise, that virtually all transgenic events, so far, taken through the deregulatory procedure are (directly or indirectly) from the private sector and carry the potential for substantial financial reward. Humanitarian projects to the benefit of the poor obviously do not fall into this category, although the benefit would apply to many millions. There is a lot of good intention world wide in the public sector to exploit the potential of green biotechnology for the benefit of the poor in developing countries. If our society, however, continues with the present "extreme precautionary" approach to bio-safety assessment, it is absolutely unrealistic to invest any further funds into public research for this purpose. Of course, there would be interesting scientific progress, but there will be no product, and especially no product passing through regulation. And, consequently, all this work will have no practical output and nobody in the target population would have any benefit.

Extreme precautionary regulation is there for a number of reasons, but none of those is justified.

Why then do we have this GMO-regulation? First of all, there are historic reasons. At the beginning of GMO-technology development it was sensible to be careful ("precautionary") and the scientists themselves - at that time working not with plants but with human-pathogenic micro-organisms - established regulations based on the notion that the consequence of the technology could lead to "unpredictable genome alterations". Experience, after more than 20 years with transgenic plants and their practical application on 50 million hectares farmland as well as from many hundreds of "biosafety" experiments in which bio-safety questions in context with transgenic plants have been carefully studied, led to numerous original publications and reports from academic institutions which all come to the conclusion, that there is no specific risk associated with the technology, which would exceed risks inherent anyhow to traditional plant breeding or natural evolution. (For a discussion on the moral imperative of the use of genetically modified crops in developing countries please see Nuffield Council On Bioethics, follow-up discussion paper January 2004, homepage www.nuffieldbioethics.org) Why then do we maintain GMO regulation and even extend it to ever more extreme precautionary regulation? The answer to this question often follows the notion that we have to do so to built trust in the technology for its acceptance by the consumer. Experience with this strategy over the last 10 years, however, demonstrates clearly that this approach did not work in Europe and many developing countries, and this is not surprising. How should a "normal" citizen understand that his/her government is regulating a technology in an extreme restrictive manner, if this technology is without specific risks. Every unbiased citizen will, of course, assume that his/her government is taking rational decisions and the technology must be as dangerous as the regulation implies. Consequently, maintenance of extreme precautionary regulation builds mistrust instead of trust. Why then do we not at least clear regulation from all scientifically unjustified and opportunistic ballast to build a rational regulatory procedure? It seems that not many institutions have an interest or the political power to do so. If we consider the potential GMO technology has with regards to food security in developing countries than numerous international organizations should have an interest, but neither FAO, nor WHO or UNIDO will have the courage and power to do so. What prize is our society paying for this opportunistic attitude towards an established "extreme precautionary regulatory" system, in function world-wide? Very clearly: GMO-technology will not reduce hunger and malnutrition, and will not protect the environment in developing countries. The use of the technology will be restricted to "luxury projects", with safe financial returns, of the private sector and in developed countries. There will, of course, be some spin-offs from these projects into developing countries, and these may even carry some benefits for the poor - such as "insect-resistant cotton", but there will be no product development focussing on urgent and specific needs of the poor in developing countries, such as "food security"!

Justification for extreme precautionary regulation ignores the basic genetic facts of traditional crop varieties.

GMO technology has the potential to support and to complement traditional plant breeding. In the context of the discussion on GMO-regulation, which is justified with the argument that genetic engineering leads to "unpredictable genome alterations" it may be helpful to remember a few basic facts concerning all our plant-based food which is derived from crop plant varieties, which, without any exception, have been developed through traditional plant breeding.

Traditional Plant breeding leads to totally unpredictable and most severe alterations of the genome.

Plant breeding is using the technique of "crossing followed by selection" to combine traits of agronomic and nutritional interest and to exclude undesired traits. Starting material for this procedure are "landraces" of crop plants, originally identified and selected by indigenous farmers. Landraces differ from each other in traits because they differ in "mutations". Mutations are "unpredictable genome alterations." In the course of traditional breeding the technology adds un-deliberately and automatically further (in parts very dramatic) "unpredictable genome alterations such as "recombinations", "translocations", "deletions", "inversions" etc. These "unpredictable" and "most severe" genome alterations are accumulated at every breeding step and each new traditionally bred variety is thus based on, and characterized by an increasing array of such genome alterations. With the progress of the breeding process varieties are combined with varieties, often with related wild relatives of the crop plants, often further altered in their genome by induced mutations. All our modern crop varieties - from which we derive our food - have a long history and are composed of numerous previous varieties and there is not the slightest doubt possible, that all our traditionally bred crop varieties are most extensively "genetically modified" by hundreds if not thousands of "unpredictable genome alterations". This is, of course, also true for those varieties used by organic farmers. We just do not call them "GMO's"!

Every traditionally bred modern crop variety is most intensively "genetically modified".

All this is exemplified in the "breeding tree" leading to IR64, the most popular Indica rice variety, developed at the International Rice Research Institute, Philippines and grown all over Southeast Asia. The pictures shows graphically how intensively the original rice genome (represented by blue boxes) has been "genetically modified" by "mutations" (yellow bars), "recombinations" (red bars), "translocations" (blue bars) and "deletions" (light-blue bars) to finally arrive at the genome of IR64. Neither this variety, nor anyone of those who have been channelled into the breeding tree have ever experienced any "bio-safety assessment" and billions of consumers in developing countries have consumed IR64 (as all the other rice or crop varieties) and survived on this and the preceding varieties without any harm, and there was no unpredictable harm to the environment as well. And this holds true for all the other varieties in all the other crops - despite of all the "most dramatic and unpredictable alterations to the genome"! Actually nobody could survive without eating food from "genetically modified" crops.

"Genetically engineered" varieties differ from the "genetically modified" ones in small, precise, similar, and well studied alterations.

For Golden Rice we have taken this variety IR64 and added two precisely defined genes into the 50 000 gene-genome of rice, using a technology which is by orders of magnitude more precise than traditional breeding, to provide pro-vitamin A in the seed to reduce vitamin A-malnutrition. This is now an example of a "genetically engineered" variety - a "GMO" - and such a plant is now falling under "extreme precautionary" regulations despite the fact, that the engineering step is, in comparison to the history of IR64 extremely small, perfectly predictable, most detailed studied and without any greater risk to the consumer or the environment. The reader is invited to find the difference between IR64 and Golden IR64 in the picture above!

There is no scientific justification to treat "genetically engineered" crops different from "genetically modified" ones.

Our experience with traditionally developed crop varieties tells us very clearly that "unpredictable genome alterations" are not an argument for extreme regulation. Why are they now, and beyond any logic, the key argument for extreme regulation of "genetically engineered" plants? The argument that genes may come from different organisms and would never have found their way into a GMO can not be accepted as well. We all know that genes are connected by a continuum in evolution and are closely related and the "crossing barrier" between species is a mechanism to advance evolution within a species, but not to prevent introduction of genes. Why are GMO's singled out from the normal breeding tree and treated according to the established rules and regulations of an extreme precautionary principle, thus preventing their sensible use to the benefit of the poor. This, to the authors understanding, is against any logic and takes us back into the historical time period of "Middle Ages" and before the "Age of Enlightenment". As this attitude is singling out "green biotechnology" from nearly all other modern technologies, it seems obvious, that there is a deliberate campaign with a hidden political agenda.

Extreme precautionary regulation without risk-benefit analysis is immoral and highly destructive.

What are the consequences of the extreme precautionary regulation of green biotechnology for public research towards food security in developing countries? There are numerous scientists and institutions in developing countries who have the capacity, motivation, and often even funding to work towards scientific progress in the areas of pest-, disease-, drought-, heat-, cold-, saline-, heavy metal resistance with the potential to rescue harvests and to expand agricultural productivity to hostile environments; to improve photosynthetic efficiency and to enhance the exploitation of natural resources to increase productivity; to enhance nutritional content to reduce malnutrition with regards to micro-nutrients such as vitamin A etc. Very few of those, however, have the financial and mental capacity to transform a scientific success into an applicable "product", which is the first prerequisite for benefit of the poor from a scientific advance. Probably no scientist nor institution in the public domain, however, have the resources, experience, and determination to carry a single GMO product across the hurdles of to days extreme precautionary regulatory procedures. Regulatory authorities in developing countries are less experienced, more insecure, and therefore, more stringent than their colleagues in developed countries. Even with support from the experienced private sector deregulation of a novel GMO product has become a gigantic task. It is, therefore, very obvious that, if we continue with the present regulatory standards, the potential of green biotechnology will not reach the poor.

In the 19th century a cultural taboo let to the tragic death of an 18 year old princes.


In the 21st century ignorance of our society leads to avoidable misery and death of millions.

"Genetically engineered" plants are not unusual plants, filled with mysterious dangers for the consumer and the environment. Europe can be proud of its cultural heritage of the "Age of Enlightenment" and should rather listen to the advice of science than that of "witch hunters". It is Europe's responsibility to help developing countries to harness the potential of green biotechnology, however the European attitude badly affects the attitude in developing countries.

Europe can afford such an extreme negative attitude because it can buy whatever it wants on the world market. However, for developing countries such an attitude leads to unnecessary death and misery of many millions. Let me close with two citations from the follow-up discussion paper of the Nuffield Council on Bioethics 2004: "The European Union is ignoring a "moral imperative" to promote genetically modified crops for their great potential for helping the developing world." "We believe EU regulators have not paid enough attention to the impact of EU regulations on agriculture in developing countries." Our societies have wasted too much time in a long phase of "risk-obsession". Stop following the "wrong prophets"! Putative benefits by far outdate the "phantom risks". It is time to return to "common sense".

Ingo Potrykus, PhD, Professor emeritus Plant Sciences,
Swiss Federal Institute of Technology (ETH), Zuerich, Switzerland