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Genetic Use Restriction Technologies:
Good for Seed Companies and Bad for Farmers?
Luca Lombardo Variety level GURTs
The term "Genetic Use Restriction Technologies" (GURTs), The molecular construction described in the patent U.S. coined in 1999 by the Subsidiary Body on Scientific, 5,723,765 provides the use of (i) a lethal gene, (ii) a repressor Technical and Technological Advice of the UN Convention gene (the gene switch) that is responsive to an external on Biological Diversity (CBD), relates to a series of stimulus, and (iii) a Cre recombinase gene – the expression experimental methods aimed at restricting the unauthorized of which is blocked by the repressor – linked together in use of genetic material by controlling gene expression a gene cassette. The lethal (or terminator) gene codes for in genetically engineered (GE) plants at the variety level the cytotoxic protein Ribosome Inactivating Protein (RIP, (V-GURTs) or at the trait level (T-GURTs). The general or saporin) and is under control of a Late Embryogenesis design provides the insertion in plants of a "genetic switch" Abundant (LEA) promoter – so that it is only transcribed activated (or inactivated) by an external – chemical or during late embryogenesis – linked to a DNA spacer physical – inducer to prevent germination in V-GURTs, or, (blocking) sequence flanked by specific excision sites (lox in the case of T-GURTs, to turn on/off a value-added trait sequence) that prevent the activation of the terminator such as tolerance to herbicides or biotic and abiotic stresses, gene. The repressor gene, a Tn10 tet repressor gene, is pest resistance, etc. under the control of a constitutively active promoter (e.g., Despite the very first patent application (granted to CaMV 35S) and encodes a protein that binds to the tet DuPont in 1994 – U.S. patent 5,364,780) containing GURT operon(s) contained in the constitutive promoter of the Cre concepts dates back to 1991, it took seven years for these recombinase gene, preventing its expression. Before being technologies to catch the world's attention, with the grant sold to the farmer, the seeds are exposed to an external of the patent U.S. 5,723,765 entitled "Control of plant gene chemical inducer (tetracycline) that prevents binding of expression" jointly owned by the United States Department the repressor to the operon. This causes transcription of of Agriculture (USDA) and Delta & Pine Land Company. the Cre Recombinase that cuts the specific excision sites The invention described in the specification was the first flanking the blocking sequence linked to the toxic gene. V-GURT, thereafter best known as "terminator technology," Consequently, during late embryogenesis, the lethal gene is and quickly became one of the most opposed genetic expressed, leading to the abortion of all embryos. Thus, the engineering biotechnologies. In fact, while the holders of seeds purchased by farmers will be able to germinate in the the patent considered the possibility for seed companies field, and the culture will develop normally, but the seeds to realize transgenic plants producing only sterile seeds produced in the harvest will be sterile and thus cannot be as a "technology protection system," public opinion, non- saved for later cropping.
governmental organisations and smallholder farmers' Other technologies have subsequently been developed associations saw it as a disadvantageous and unethical for producing sterile seeds. The patent AU 621195 B2 mechanism to force farmers to purchase new seeds every owned by Zeneca describes an embodiment in which year, preventing the practice of seed saving (also "brown- a gene encoding a disrupter protein is permanently bagging") estimated to account for between 15% and 20% active in the seed, making it sterile. The gene promoter of the world's food supply involving 1.4 billion people1. is under the control of a specific operator sequence. A As a consequence of the strong protests all over the world, further repressor protein, whose gene is under control of the CBD Decision V/5 section III of the Fifth Conference a chemically inducible promoter, can bind to the operator of the Parties (COP5) held in Nairobi in June 2000 imposed sequence controlling the promoter of the disrupter protein a de facto global moratorium on this technology, ratified gene, inhibiting its expression. The breeder must apply the by specific national laws in India, Canada and Brazil. The chemical inducer during the process of seed multiplication, moratorium was upheld in March 2006 during the eighth interrupting the application only at the time of selling the Ordinary Meeting of the Conference of the Parties (COP8) seeds.
held in Curitiba, Brazil, so that to date, in spite of the over The recoverable block of function (RBF) developed 40 granted or submitted patent families (groups of patents in tobacco by Kuvshinov et al.2 exploits the barnase/ that include identical or similar applications) related to barstar gene system. The barnase gene, under control of GURTs, no plant with these characteristics has been either a sulphydryl endopeptidase promoter active at the time of approved or marketed anywhere in the world. seedpod development, encodes a potent ribonuclease that in embryos and sprouts confers cell death or prevents sexual reproduction. In the RBF, barnase is inserted in an artificial a trait by means of chemical treatment or environmental intron within the gene of interest; the same insert contains factors. The mechanism described in the Zeneca patent a second inducible sequence: a barstar, which is a strong WO 9403619 is quite similar to the one described in the repressor gene that prevents barnase action.This recovering terminator technology patent. The gene responsible for the action is induced by an external stimulus such as chemical production of a toxin/disrupter protein can be selectively application or heat shock; therefore, if seeds are exposed activated or inactivated without killing the embryo by to the chemical, they will express the normal phenotype, applying or withholding the inducer chemical before the otherwise they will die. Because of this reversible sterility, seed is sold. Consequently, the first generation plant is activists dubbed RBF "zombie technology." capable of expressing the trait of interest, but the second A further strategy patented by Zeneca (Syngenta) generation is not. This is why T-GURTs are known as in 2001 was designed to increase the "shelf life" of "traitor technologies." In another method, the application vegetatively reproduced species such as tuber and root of a chemical inducer activates the expression of a silenced crops and ornamental plants through the insertion of a gene, e.g., by anti-sense suppression, encoding the trait of permanently active gene able to block the growth of the interest.
plants or plants' organs. The transgene can also be excised using recombination systems like ParA-MRS, Bxb1-att, R-RS, Cre-lox, or FLP- FRT. The introduced recombinase removes itself and the The technically but not conceptually equivalent version transgene after chemical or heat shock treatment.
of the terminator technology in the animal kingdom is the Eventually, Ardell4 classified his own patent application so-called RIDL (Release of Insects carrying a Dominant entitled "Genetic encryption" as a GURT. This invention Lethal) technology. This technique, under development assumes that genetically altering the anticodon-stem by Oxford Insect Technologies (Oxitec), was employed loop (ASL) templates of tRNA genes in situ changes the for creating sterile offspring in insect vectors of diseases codon reading specificity of the deriving tRNA, inducing (such as dengue fever and malaria) or agricultural insect a functional alteration of the genetic code able to produce pests. The RIDL system requires that a strain of the target proteins with an intended structure only when translated insect carries a conditional, dominant, sex-specific lethal within the context of that specifically engineered organism gene activated by the expression of the tetracycline- or in vitro translation system. repressible transactivator fusion protein (tTA), in turn, under the control of a suitable (constitutive, female- Possible benefits
specific, embryo-specific, etc.) promoter3. tTA is a hybrid, As previously written, GURTs were basically conceived to synthetic transcription factor resulting from the fusion protect genetic resources and innovations by preventing seed of the prokaryotic (bacterial) Tet repressor TetR – a saving. Indeed, hybridisation is a commonly used biological sequence-specific DNA binding protein – with a eukaryotic means to prevent seed saving practices, as the out-crossing transcriptional transactivation domain (most widely used so that occurs in the subsequent generations will (generally) far is the acidic domain of herpes simplex virus VP16). In generate plants with lower vigour or uniformity. However, the absence of tetracycline, tTA binds, by means of its tetR in many self-fertilising crops such as rice, wheat, cotton, domain, a short, specific, DNA sequence called tet operator etc., the protection of genetic resources via hybridization (tetO) and acts as a transcriptional activator of the lethal may be infeasible, while GURTs could potentially be gene through the VP16 transcriptional activation domain, applied to all seed-propagated crops. Similarly, despite leading the insect to death. Tetracycline, generally added in the fact that intellectual property protection of new plant the diet, prevents the tTA-tetO bond, allowing the insects to varieties is granted both at the local (by patents or plant be reared in manufacturing facilities. When the transgenic varietal protection – PVP) and at the international level (by tTA insects are released in the environment, the permissive the International Union for the Protection of New Varieties condition – tetracycline – is not encountered by the wild of Plants – UPOV – and by the WTO Trade-Related Aspects population; consequently, the expression of the lethal gene of Intellectual Property Rights – TRIPS – Agreement), will cause mortality in the early developmental stages of and despite the additional fact that the purchasers of seeds the heterozygous progeny but will not affect the viability containing a patented GE trait (e.g., in Roundup Ready of the GE parent, provoking an effective control of the wild crops by Monsanto) are required to sign a contract agreeing pest population. not to save second-generation seeds for replanting, these social means to restrict the unauthorized use of genetic Trait level GURTs
material have been often proved to be ineffective or at least Several methods have been proposed to switch on or off time- and money-consuming. Moreover GURTs would guarantee that farmers would be dependent on the purchase The replacement of diverse ecotypes with a few uniform of new seeds and chemical inducers even after the expiry of varieties, as well as the potentially massive use of chemicals licenses; at the same time, farmers would benefit from the to treat the seeds each year might have a detrimental effect improved new plant varieties. GURTs would also prevent on soil microflora and fauna, and increase the prevalence of competitor biotech industries from using seeds in their own antibiotic-resistant bacteria. GURT-transformed crops might breeding programmes, which could encourage investment also produce low quantities of autotoxic compounds with in research and development in the plant-breeding sector negative impacts on non-target organisms, and eventually, of the seed companies that could favour a decrease in as food/feed, transfer allergenicity and antibiotic resistance.
selling prices and food costs, and, paradoxically, increase Further issues relate to the effectiveness of GURTs in preventing transgene escape. In fact, since the GURT Other possible advantages of GURT technology are engineered seeds and plants would require a 100% effective related to the environmental containment of transgenic application of the chemical inducer to prevent the escape seeds (V-GURT) or the prevention of unwanted transgene of a non-functioning transgene via both seed and pollen, flow (T-GURT), which are among the greatest concerns some seeds and plants may not respond or may not take associated with GE crops, thus facilitating their public up enough inducer to activate the repressor gene, thereby acceptance. Furthermore, GURTs might allow the breeding producing fertile GM plants. companies to circumvent any legal disputes due to Other technical criticisms5 of the GURT technology transgene introgression into wild populations, either for refer to the proper segregation of multiple genes during food or biopharm crops. reproduction, escape of genes over generations, involuntary response to natural or artificial related compounds, Concerns
accidental switching on of sleeper genes, the instability The principal complaint against GURTs is that farmers of the promoters, and the horizontal flow of genetically would be forced to buy seeds and the chemicals required modified pollen to non-target organisms.
to switch on the value-added trait each year, which could further impoverish poor farmers and would increase Conclusion
farmers' dependence on multinational seed corporations. To date, GURTs are only a theoretical design; nevertheless, This could also reduce farmers' food security and erode in the light of the hypothetical pros and cons discussed in their traditional knowledge and capacity for innovation the text, it is difficult to make a definitive judgment on them. of informal crop genetic improvement, since the adapted On the one hand, T-GURTs could allow farmers to decide or selected autochthonous cultivars would be replaced by whether, and possibly when, to activate a valuable trait and the new GURT-protected varieties, resulting in loss of the so would not affect the traditional conservation practices local genetic diversity. GURTs could limit access to genetic and exchange of seeds, offering at the same time a solution resources and the fair and equitable sharing of benefits to the problem of genetic pollution by preventing the spread arising from their utilization enshrined in the Nagoya of the engineered traits. On the other, the ethical concerns Protocol and would cause the displacement of local farming against V-GURTs that led to the global moratorium seem systems and the social, cultural, and spiritual dimensions too strong to overcome and will surely play a preeminent associated with them.
role in the future social and political debate. 1. Shand H. (2012) The Big Six: A Profile of Corporate Power in Seeds, Agrochemicals & Biotech. The Heritage Farm Companion 11-15.
2. Kuvshinov V., Koivu K., Kanerva A., Pehu E. (2001) Molecular control of transgene escape from genetically modified plants. Plant Science 160(3):517-522. 3. Gossen M., Bujard H. (1992) Tight control of gene expression in mammalian cells by tetracycline-responsive promoters. Proceedings of the National Acad- emy of Sciences, USA, 89:5547–5551.
4. Ardell, D.H. (2013) Genetic Encryption. US patent 8592199 B2. 5. Daniell, H. (2002) Molecular Strategies for Gene Containment in Transgenic Crops. Nat. Biotechnol. 20, 581-586. Luca Lombardo, Ph.D. Department of Crop Systems, Forestry and Environmental Sciences University of Basilicata, Via Nazario, Sauro 85 - 85100 Potenza, Italy

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