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Golden Rice regulatory issues

Regulation, the toughest hurdle so far

We need a system that builds upon accumulated experience

Unjustified and impractical legal requirements are preventing genetically engineered crops from saving millions of people, especially children, from starvation and malnutrition, says Ingo Potrykus in a Nature Opinion Paper pdf.

It took ten years —from 1980 to 1990— to develop the technology to introduce genes into rice. It took another nine years —from 1990 to 1999— to identify and introduce the genes necessary to relaunch the carotene biosynthetic pathway in the rice grain, resulting in the Golden Rice prototype obtained by Ingo Potrykus at the ETH in Zurich. After that, scientists in Freiburg and at Syngenta worked together to generate improved versions of Golden Rice.

In 2012 we're still awaiting regulatory approval to finally reach the first group of farmers. Considering the enormous humanitarian potential of Golden Rice in reducing blindness (500,000 children per year) and infant mortality (2-3 million deaths per year), it is hardly understandable that lobby groups and the authorities have not learnt enough from the experience accumulated so far to make the regulatory process more science based.

During the last 20 years a vast knowledge base regarding the production and commercialisation of transgenic plants has been amassed. While the Golden Rice Humanitarian Board understands that every new transgenic event must comply with regulations to guarantee the safety of any product derived from it, its members have a hard time dealing with non-scientific arguments that are unnecessarily delaying the adoption of the technology while ignoring the human tragedy brought about by vitamin A deficiency. Countries where Golden Rice could provide health benefits should be provided with the opportunity to pursue their own independent decision-making process and not held hostage by unfounded and self-serving external pressures.

The Golden Rice Humanitarian Board supports efforts to develop appropriate risk management strategies that can deal with acceptable risk levels, ie, especially where the benefits outnumber the potential dangers by far, as is the case with Golden Rice. Reputed ecologists, including opponents of the technology, have so far concluded that Golden Rice poses no imaginable risk to the environment. All plants produce high amounts of carotenoids, thus their presence in the grain will not introduce any new substances into the environment nor will they provide any additional selection advantage that could turn Golden Rice into a noxious weed.

Safety assessment scheme

This table gives a clear overview of the steps required to take an application through the risk assessment process (Koenig et al. 2004. Food and Chemical Toxicology 42:1047-1088). While the aim of every single step is makes sense, in principle, the detailed requirements go beyond a science-based approach, and the fact that regulations are not becoming simpler, based on the experience gained over the years, is inconsistent, to say the least.

An unbearable financial burden

What are the regulatory requirements standing in the way of Golden Rice deployment? First of all, the application should be for a carefully selected, regulatory clean transgenic event. Criteria are not necessarily based on scientific grounds; they include a number of requirements pertaining to the introduced genetic construct, eg, the inserted DNA fragment should not have undergone multiple integrations or rearrangements, there should be no read-through across the construct borders or any residual ballast DNA. This in turn requires the production of many hundreds of transgenic events using the same DNA construct, from which the regulatory clean event is then selected. The makeup of the construct itself must have been conceived taking into account the requirements imposed by the regulatory authorities. The carefully selected event can then be used to start a series of mandatory biosafety assessment experiments expected to prove or disprove any putative biosafety hazard.

The consequence of this approach is that nearly 99% of all transgenic events, and often those with the highest levels of expression, must be discarded. Already, the first step of mass production of many hundreds of similar events and the subsequent destruction of most of them is beyond reach for most public research institutions, in developing as well as in developed countries, and funding agencies are not in a position to carry such exorbitant costs.

The biosafety assessment starts with event-independent studies, related to the introduced genes and their function, and are valid for all events produced with these genes. These studies are followed by exposure evaluation tests for the novel trait, its intended use and bioavailability, as would be the case for a product like β-carotene. This study alone takes about three years, because during the pre-field trial phase the materials have to be produced in dedicated plant growth chambers and greenhouses, which is very expensive and where production levels are low.

Next on the list are protein production and equivalence analyses for the proteins encoded by the introduced genes. For this purpose the proteins have to be isolated from the plant, characterised biochemically, and their function confirmed. Further studies include a demonstration of lack of homology to known toxins and allergens, gastric degradation studies, heat stability, and acute toxicity tests in rodent feeding experiments.

This all would seem reasonable if it were not for the fact that most people have been eating these genes and their products from a number of other food sources throughout their lives. At one point, somebody even suggested to analyse whether known daffodil toxins had been introduced into Golden Rice along with the daffodil gene used to reconstitute the β-carotene biosynthetic pathway, which is totally devoid of a scientific basis: what has been transferred is one defined DNA sequence which is homologous to related genes in other organisms, and which performs exactly the same function, with no relation whatsoever to any toxin or allergen. These studies take at least two years of intensive work in a well equipped biochemistry laboratory.

The event-dependent studies are even more cumbersome; they include:

  • Molecular characterisation and genetic stability: data on single-copy effect; marker gene at same locus; simple integration; Mendelian inheritance, including phenotypic and biochemical evidence for stability 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 size limited to the minimum necessary; resequencing of insert and flanking regions.
  • Expression profiling: gene expression levels at key growth stages; evidence of seed-specific expression.
  • Phenotypic analysis: field performance, typical agronomic traits, yield compared to isogenic lines; pest and disease status must be same as parent(unexpected improvements are not tolerated).
  • Compositional analysis: data from growing the event over two seasons at six locations in three replicates on proximates, macro and micronutrients, antinutrients, toxins, allergens; data must be generated on modified and isogenic backgrounds.
  • Environmental risk assessment: this type of analysis takes 4-5 years of work by an entire research team.

It is obvious that no scientist or scientific institution in the public domain has the potential, funding or motivation to perform such lengthy and expensive biosafety experiments. It comes as no surprise then that virtually all transgenic events that have been carried through the deregulatory process so far are &endash;directly or indirectly&endash; in the private sector and are restricted to high-value crops. Humanitarian projects do not fall into this category, even though they would benefit millions of people. There is a lot of goodwill in the public and in the private sectors worldwide to exploit the potential of green biotechnology for the benefit of the poor. However, without a realistic risk assessment approach, funds for public research will not be capable of doing the trick. Scientific progress in the public sector has thus become detached from product development, and the population at large is not benefiting from that progress.