Does RNAi-Based Technology Fit within EU Sustainability Goals?

Abstract

European Union (EU) and global sustainability policies emphasize the need to replace contentious pesticides with safe, efficient, and cost-effective alternatives to ensure sustainable food production. However, R&D for alternatives to contentious pesticides are lagging behind and need to be broadened. Here, we discuss how RNAi-based technology can contribute to pesticide risk reduction. European Union (EU) and global sustainability policies emphasize the need to replace contentious pesticides with safe, efficient, and cost-effective alternatives to ensure sustainable food production. However, R&D for alternatives to contentious pesticides are lagging behind and need to be broadened. Here, we discuss how RNAi-based technology can contribute to pesticide risk reduction. Future Agriculture: Ensuring Sustainable Food Production in the EUThe Farm-to-Fork (F2F) strategyi, one of the pillars underneath the European Commission’s new Green Deal, aims to ensure a more sustainable and food-secure society. Its aims include a reduction in agrochemical inputs, such as pesticides, fertilizers, and antimicrobials, to achieve greater sustainability and health, and reduce loss of biodiversity while ensuring continued crop protection. It envisages various practices that promote lesser pesticide usage, such as integrated pest management (IPM), and the use of precision agriculture and artificial intelligence. It also recommends imposing maximum levels (tolerances) for pesticide residues in imported commodities to enforce sustainable production and pesticide use in countries exporting to the EU. The F2F strategy’s pesticide reduction measures are also cited by the Commission’s concurrent Biodiversity Strategy 2030ii, as a means towards reversing the alarming decline in farmland birds and insects (especially pollinating ones). It also proposes IPM and the establishment of variable landscapes hospitable to natural pest regulators. Furthermore, it envisages organic farming to cover 25% of agricultural land in 2030, and it suggests establishing forests that are resilient towards pests, and the banning of chemical pesticides from use in urban green spaces.At the same time, the Commission also published a report on the experience gained with its policy towards more sustainable use of pesticides under the so-called ‘Sustainable Use Directive’ (SUD) of 2009iii. Under the SUD, EU member states had to develop and implement national action plans for the reduction of pesticide volumes and risk. The report concluded that one prevalent shortcoming across the board was the lack of assessment of the actual implementation of IPM practices, while there was an upward trend in non-chemical, low-risk, and basic active substances, and it also concluded that the R&D basis for such alternatives should be broadened. Notably, the European pesticide and biopesticide producers’ organization (European Crop Protection Association; ECPA) recently pledged to support these with various commitments focused on innovation, sustainability, and health, including a €14 billion investment in the development of precision agricultural techniques for the more targeted (hence reduced) application of pesticides, and of natural biopesticides with favorable IPM characteristics, complementing other pesticidesiv. Concurrent with the EU’s policy towards less risky pesticides, the United Nations Environmental Program (UNEP), other international and national organizations, and companies are proactively pursuing risk reduction for ‘highly hazardous pesticides’.As already noted in the review of the SUD implementation, R&D for alternatives to chemical pesticides has been lagging behind and needs to be broadened. The new EU policies make the case for innovative, enabling technologies using versatile platforms for the development of agents that are widely applicable to a host of different crop pests and diseases, yielding products with high specificity for the targeted pest or disease, a benign environmental and health profile, and requiring a short development time and affordable in costs.RNAi-Based Technology Enables Pesticide Risks Reduction GoalsRNAi is a well-known natural biological process in most eukaryotes, where double-stranded RNA (dsRNA) molecules regulate gene expression by targeting specific endogenous mRNA molecules in a sequence-specific manner (Figure 1). By exploiting this sequence-dependent mode of action, RNAi-based products with higher selectivity and better safety profiles (less mobile through the soil, less persistent, and less toxic) compared with contentious chemical pesticides are being developed [1.Wang M. et al.Bidirectional cross-kingdom RNAi and fungal uptake of external RNAs confer plant protection.Nat. Plants. 2016; 2: 1-10Crossref Scopus (339) Google Scholar, 2.Koch A. et al.An RNAi-based control of Fusarium graminearum infections through spraying of long dsRNAs involves a plant passage and is controlled by the fungal silencing machinery.PLoS Pathog. 2016; 12e1005901Crossref PubMed Scopus (257) Google Scholar, 3.Mitter N. et al.Clay nanosheets for topical delivery of RNAi for sustained protection against plant viruses.Nat. Plants. 2017; 3: 1-10Crossref Scopus (400) Google Scholar, 4.Jin S. et al.Engineered chloroplast dsRNA silences cytochrome p450 monooxygenase, V-ATPase and chitin synthase genes in the insect gut and disrupts Helicoverpa armigera larval development and pupation.Plant Biotechnol. J. 2017; 15: 145Crossref PubMed Scopus (3) Google Scholar]. RNAi-based control has several unique features that offer additional opportunities compared with contentious chemical pesticides. The dsRNA active molecules can be designed to target the expression of different genes without the need to change the sequence-dependent mode of action and, depending on the gene targeted in the pest, various outcomes ranging from sublethal to lethal effects can be achieved. Although selecting effective RNAi targets can be a challenging step, a combination of the availability of in silico tools and an increase in the availability of genome databases for various species has made it possible to design species-selective and efficient dsRNA molecules with zero to negligible off-target effects in non-target species [5.Bachman P.M. et al.Ecological risk assessment for DvSnf7 RNA: a plant-incorporated protectant with targeted activity against western corn rootworm.Regul. Toxicol. Pharmacol. 2016; 81: 77-88Crossref PubMed Scopus (61) Google Scholar,6.Taning C.N.T. et al.A sequence complementarity-based approach for evaluating off-target transcript knockdown in Bombus terrestris, following ingestion of pest-specific dsRNA.J. Pest. Sci. 2021; 94: 487-503Crossref Scopus (12) Google Scholar]. This presents an advantage contentious chemical pesticides with action non-target dsRNA is a natural that is by and P.M. et and of dsRNA in soil, and Sci. PubMed Scopus Google et of RNA and of double-stranded RNA molecules in agricultural Sci. PubMed Scopus Google in to chemical pesticides with in the can be using in delivery through or application of RNAi-based products (Figure RNAi-based from most other new the gene to the expression of dsRNA molecules with high target specificity as active the short are mobile in the plant to et of endogenous RNAs of and in Google Scholar]. This of dsRNA application is of to and are in and new the trend the development of RNAi-based products for application against crop pests is with dsRNAs are et in agricultural of topical RNAi in 2017; 81: Scopus Google Scholar]. products can also be using agricultural practices, such as for or through in The of applicable RNAi-based products with high target pest selectivity and a better safety has also the of various companies the that tools to support the development of these products for for of and control with the double-stranded active to be specific to an gene in the pest or while for non-target The increase in availability of databases for more and the development of such as and gene expression has the of RNAi Although in silico tools can in the design of pest or dsRNA from is to support against the and zero to negligible effects in non-target are dsRNA application for RNAi-based one approach involves the in expression of RNAi to target genes of while the approach involves the application of The of the application on the the crop and the and on the of an efficient application against the delivery the development with the in approach under while the approach is to under the plant protection The approach can be by a lack of tools to plant high of production to of the and to The approach is by the high of dsRNA for application and the lack of technologies to RNAi against these delivery to the development of and effective RNAi-based can contribute to agricultural sustainability by the use of contentious a of the the production for dsRNA molecules be in the to the global with to the of of The same platforms be to dsRNA production less for for agricultural This promote the cost-effective of volumes of dsRNA for pesticide Furthermore, are being made in the development of technologies for the delivery of dsRNA molecules to target crop pests or N. et al.Clay nanosheets for topical delivery of RNAi for sustained protection against plant viruses.Nat. Plants. 2017; 3: 1-10Crossref Scopus (400) Google Scholar]. are designed to dsRNA ensure effective delivery of dsRNA to pests or RNAi the can be challenging and on the and pests or risk assessment for dsRNA should be on a a time the EU is towards sustainability with reduction in contentious pesticides, the of to the development of RNAi-based products with a better et in and of and endogenous RNAi technologies for Biotechnol. PubMed Scopus Google with the of companies to support that RNAi-based pest control can contribute to the EU pesticide reduction in the F2F and of to pesticides policy needs towards sustainability, an of et PubMed Scopus Google and a widely in a for the of pesticides been as risk with effects of pesticides et risk and of and a review of the Scopus Google Scholar]. It is to include the of and to also that are to make to new of pesticides. be the in of RNAi-based other such as the to the application is to be or or N. et risk and with different of a of and of of PubMed Scopus Google Scholar]. it is of to develop with to ensure that and are on in the development process of RNAi-based control the of towards RNAi-based control a of the is et and change towards to food Sci. PubMed Scopus Google such an is to be by external including the of of RNAi-based products the from such that of RNAi-based control and Future sequence-specific mode of action of RNAi-based products unique in selectivity and compared with other and suggests as a to contentious pesticides or reduce in However, to to RNAi-based several to be The of and RNAi-based products in with under the and by the greater and of Furthermore, an in the of sustainable products for crop protection. Future Agriculture: Ensuring Sustainable Food Production in the EUThe Farm-to-Fork (F2F) strategyi, one of the pillars underneath the European Commission’s new Green Deal, aims to ensure a more sustainable and food-secure society. Its aims include a reduction in agrochemical inputs, such as pesticides, fertilizers, and antimicrobials, to achieve greater sustainability and health, and reduce loss of biodiversity while ensuring continued crop protection. It envisages various practices that promote lesser pesticide usage, such as integrated pest management (IPM), and the use of precision agriculture and artificial intelligence. It also recommends imposing maximum levels (tolerances) for pesticide residues in imported commodities to enforce sustainable production and pesticide use in countries exporting to the EU. The F2F strategy’s pesticide reduction measures are also cited by the Commission’s concurrent Biodiversity Strategy 2030ii, as a means towards reversing the alarming decline in farmland birds and insects (especially pollinating ones). It also proposes IPM and the establishment of variable landscapes hospitable to natural pest regulators. Furthermore, it envisages organic farming to cover 25% of agricultural land in 2030, and it suggests establishing forests that are resilient towards pests, and the banning of chemical pesticides from use in urban green spaces.At the same time, the Commission also published a report on the experience gained with its policy towards more sustainable use of pesticides under the so-called ‘Sustainable Use Directive’ (SUD) of 2009iii. Under the SUD, EU member states had to develop and implement national action plans for the reduction of pesticide volumes and risk. The report concluded that one prevalent shortcoming across the board was the lack of assessment of the actual implementation of IPM practices, while there was an upward trend in non-chemical, low-risk, and basic active substances, and it also concluded that the R&D basis for such alternatives should be broadened. Notably, the European pesticide and biopesticide producers’ organization (European Crop Protection Association; ECPA) recently pledged to support these with various commitments focused on innovation, sustainability, and health, including a €14 billion investment in the development of precision agricultural techniques for the more targeted (hence reduced) application of pesticides, and of natural biopesticides with favorable IPM characteristics, complementing other pesticidesiv. Concurrent with the EU’s policy towards less risky pesticides, the United Nations Environmental Program (UNEP), other international and national organizations, and companies are proactively pursuing risk reduction for ‘highly hazardous pesticides’.As already noted in the review of the SUD implementation, R&D for alternatives to chemical pesticides has been lagging behind and needs to be broadened. The new EU policies make the case for innovative, enabling technologies using versatile platforms for the development of agents that are widely applicable to a host of different crop pests and diseases, yielding products with high specificity for the targeted pest or disease, a benign environmental and health profile, and requiring a short development time and affordable in The Farm-to-Fork (F2F) strategyi, one of the pillars underneath the European Commission’s new Green Deal, aims to ensure a more sustainable and food-secure society. Its aims include a reduction in agrochemical inputs, such as pesticides, fertilizers, and antimicrobials, to achieve greater sustainability and health, and reduce loss of biodiversity while ensuring continued crop protection. It envisages various practices that promote lesser pesticide usage, such as integrated pest management (IPM), and the use of precision agriculture and artificial intelligence. It also recommends imposing maximum levels (tolerances) for pesticide residues in imported commodities to enforce sustainable production and pesticide use in countries exporting to the EU. The F2F strategy’s pesticide reduction measures are also cited by the Commission’s concurrent Biodiversity Strategy 2030ii, as a means towards reversing the alarming decline in farmland birds and insects (especially pollinating ones). It also proposes IPM and the establishment of variable landscapes hospitable to natural pest regulators. Furthermore, it envisages organic farming to cover 25% of agricultural land in 2030, and it suggests establishing forests that are resilient towards pests, and the banning of chemical pesticides from use in urban green the same time, the Commission also published a report on the experience gained with its policy towards more sustainable use of pesticides under the so-called ‘Sustainable Use Directive’ (SUD) of 2009iii. Under the SUD, EU member states had to develop and implement national action plans for the reduction of pesticide volumes and risk. The report concluded that one prevalent shortcoming across the board was the lack of assessment of the actual implementation of IPM practices, while there was an upward trend in non-chemical, low-risk, and basic active substances, and it also concluded that the R&D basis for such alternatives should be broadened. Notably, the European pesticide and biopesticide producers’ organization (European Crop Protection Association; ECPA) recently pledged to support these with various commitments focused on innovation, sustainability, and health, including a €14 billion investment in the development of precision agricultural techniques for the more targeted (hence reduced) application of pesticides, and of natural biopesticides with favorable IPM characteristics, complementing other pesticidesiv. Concurrent with the EU’s policy towards less risky pesticides, the United Nations Environmental Program (UNEP), other international and national organizations, and companies are proactively pursuing risk reduction for ‘highly hazardous already noted in the review of the SUD implementation, R&D for alternatives to chemical pesticides has been lagging behind and needs to be broadened. The new EU policies make the case for innovative, enabling technologies using versatile platforms for the development of agents that are widely applicable to a host of different crop pests and diseases, yielding products with high specificity for the targeted pest or disease, a benign environmental and health profile, and requiring a short development time and affordable in Technology Enables Pesticide Risks Reduction GoalsRNAi is a well-known natural biological process in most eukaryotes, where double-stranded RNA (dsRNA) molecules regulate gene expression by targeting specific endogenous mRNA molecules in a sequence-specific manner (Figure 1). By exploiting this sequence-dependent mode of action, RNAi-based products with higher selectivity and better safety profiles (less mobile through the soil, less persistent, and less toxic) compared with contentious chemical pesticides are being developed [1.Wang M. et al.Bidirectional cross-kingdom RNAi and fungal uptake of external RNAs confer plant protection.Nat. Plants. 2016; 2: 1-10Crossref Scopus (339) Google Scholar, 2.Koch A. et al.An RNAi-based control of Fusarium graminearum infections through spraying of long dsRNAs involves a plant passage and is controlled by the fungal silencing machinery.PLoS Pathog. 2016; 12e1005901Crossref PubMed Scopus (257) Google Scholar, 3.Mitter N. et al.Clay nanosheets for topical delivery of RNAi for sustained protection against plant viruses.Nat. Plants. 2017; 3: 1-10Crossref Scopus (400) Google Scholar, 4.Jin S. et al.Engineered chloroplast dsRNA silences cytochrome p450 monooxygenase, V-ATPase and chitin synthase genes in the insect gut and disrupts Helicoverpa armigera larval development and pupation.Plant Biotechnol. J. 2017; 15: 145Crossref PubMed Scopus (3) Google Scholar]. RNAi-based control has several unique features that offer additional opportunities compared with contentious chemical pesticides. The dsRNA active molecules can be designed to target the expression of different genes without the need to change the sequence-dependent mode of action and, depending on the gene targeted in the pest, various outcomes ranging from sublethal to lethal effects can be achieved. Although selecting effective RNAi targets can be a challenging step, a combination of the availability of in silico tools and an increase in the availability of genome databases for various species has made it possible to design species-selective and efficient dsRNA molecules with zero to negligible off-target effects in non-target species [5.Bachman P.M. et al.Ecological risk assessment for DvSnf7 RNA: a plant-incorporated protectant with targeted activity against western corn rootworm.Regul. Toxicol. Pharmacol. 2016; 81: 77-88Crossref PubMed Scopus (61) Google Scholar,6.Taning C.N.T. et al.A sequence complementarity-based approach for evaluating off-target transcript knockdown in Bombus terrestris, following ingestion of pest-specific dsRNA.J. Pest. Sci. 2021; 94: 487-503Crossref Scopus (12) Google Scholar]. This presents an advantage contentious chemical pesticides with action non-target dsRNA is a natural that is by and P.M. et and of dsRNA in soil, and Sci. PubMed Scopus Google et of RNA and of double-stranded RNA molecules in agricultural Sci. PubMed Scopus Google in to chemical pesticides with in the can be using in delivery through or application of RNAi-based products (Figure RNAi-based from most other new the gene to the expression of dsRNA molecules with high target specificity as active the short are mobile in the plant to et of endogenous RNAs of and in Google Scholar]. This of dsRNA application is of to and are in and new the trend the development of RNAi-based products for application against crop pests is with dsRNAs are et in agricultural of topical RNAi in 2017; 81: Scopus Google Scholar]. products can also be using agricultural practices, such as for or through in The of applicable RNAi-based products with high target pest selectivity and a better safety has also the of various companies the that tools to support the development of these products for a of the the production for dsRNA molecules be in the to the global with to the of of The same platforms be to dsRNA production less for for agricultural This promote the cost-effective of volumes of dsRNA for pesticide Furthermore, are being made in the development of technologies for the delivery of dsRNA molecules to target crop pests or N. et al.Clay nanosheets for topical delivery of RNAi for sustained protection against plant viruses.Nat. Plants. 2017; 3: 1-10Crossref Scopus (400) Google Scholar]. are designed to dsRNA ensure effective delivery of dsRNA to pests or RNAi the can be challenging and on the and pests or risk assessment for dsRNA should be on a a time the EU is towards sustainability with reduction in contentious pesticides, the of to the development of RNAi-based products with a better et in and of and endogenous RNAi technologies for Biotechnol. PubMed Scopus Google with the of companies to support that RNAi-based pest control can contribute to the EU pesticide reduction in the F2F RNAi is a well-known natural biological process in most eukaryotes, where double-stranded RNA (dsRNA) molecules regulate gene expression by targeting specific endogenous mRNA molecules in a sequence-specific manner (Figure 1). By exploiting this sequence-dependent mode of action, RNAi-based products with higher selectivity and better safety profiles (less mobile through the soil, less persistent, and less toxic) compared with contentious chemical pesticides are being developed [1.Wang M. et al.Bidirectional cross-kingdom RNAi and fungal uptake of external RNAs confer plant protection.Nat. Plants. 2016; 2: 1-10Crossref Scopus (339) Google Scholar, 2.Koch A. et al.An RNAi-based control of Fusarium graminearum infections through spraying of long dsRNAs involves a plant passage and is controlled by the fungal silencing machinery.PLoS Pathog. 2016; 12e1005901Crossref PubMed Scopus (257) Google Scholar, 3.Mitter N. et al.Clay nanosheets for topical delivery of RNAi for sustained protection against plant viruses.Nat. Plants. 2017; 3: 1-10Crossref Scopus (400) Google Scholar, 4.Jin S. et al.Engineered chloroplast dsRNA silences cytochrome p450 monooxygenase, V-ATPase and chitin synthase genes in the insect gut and disrupts Helicoverpa armigera larval development and pupation.Plant Biotechnol. J. 2017; 15: 145Crossref PubMed Scopus (3) Google Scholar]. RNAi-based control has several unique features that offer additional opportunities compared with contentious chemical pesticides. The dsRNA active molecules can be designed to target the expression of different genes without the need to change the sequence-dependent mode of action and, depending on the gene targeted in the pest, various outcomes ranging from sublethal to lethal effects can be achieved. Although selecting effective RNAi targets can be a challenging step, a combination of the availability of in silico tools and an increase in the availability of genome databases for various species has made it possible to design species-selective and efficient dsRNA molecules with zero to negligible off-target effects in non-target species [5.Bachman P.M. et al.Ecological risk assessment for DvSnf7 RNA: a plant-incorporated protectant with targeted activity against western corn rootworm.Regul. Toxicol. Pharmacol. 2016; 81: 77-88Crossref PubMed Scopus (61) Google Scholar,6.Taning C.N.T. et al.A sequence complementarity-based approach for evaluating off-target transcript knockdown in Bombus terrestris, following ingestion of pest-specific dsRNA.J. Pest. Sci. 2021; 94: 487-503Crossref Scopus (12) Google Scholar]. This presents an advantage contentious chemical pesticides with action non-target dsRNA is a natural that is by and P.M. et and of dsRNA in soil, and Sci. PubMed Scopus Google et of RNA and of double-stranded RNA molecules in agricultural Sci. PubMed Scopus Google in to chemical pesticides with in the RNAi-based can be using in delivery through or application of RNAi-based products (Figure RNAi-based from most other new the gene to the expression of dsRNA molecules with high target specificity as active the short are mobile in the plant to et of endogenous RNAs of and in Google Scholar]. This of dsRNA application is of to and are in and new the trend the development of RNAi-based products for application against crop pests is with dsRNAs are et in agricultural of topical RNAi in 2017; 81: Scopus Google Scholar]. products can also be using agricultural practices, such as for or through in The of applicable RNAi-based products with high target pest selectivity and a better safety has also the of various companies the that tools to support the development of these products for a of the the production for dsRNA molecules be in the to the global with to the of of The same platforms be to dsRNA production less for for agricultural This promote the cost-effective of volumes of dsRNA for pesticide Furthermore, are being made in the development of technologies for the delivery of dsRNA molecules to target crop pests or N. et al.Clay nanosheets for topical delivery of RNAi for sustained protection against plant viruses.Nat. Plants. 2017; 3: 1-10Crossref Scopus (400) Google Scholar]. are designed to dsRNA ensure effective delivery of dsRNA to pests or RNAi the can be challenging and on the and pests or risk assessment for dsRNA should be on a a time the EU is towards sustainability with reduction in contentious pesticides, the of to the development of RNAi-based products with a better et in and of and endogenous RNAi technologies for Biotechnol. PubMed Scopus Google with the of companies to support that RNAi-based pest control can contribute to the EU pesticide reduction in the F2F and of to pesticides policy needs towards sustainability, an of et PubMed Scopus Google and a widely in a for the of pesticides been as risk with effects of pesticides et risk and of and a review of the Scopus Google Scholar]. It is to include the of and to also that are to make to new of pesticides. be the in of RNAi-based other such as the to the application is to be or or N. et risk and with different of a of and of of PubMed Scopus Google Scholar]. it is of to develop with to ensure that and are on in the development process of RNAi-based control the of towards RNAi-based control a of the is et and change towards to food Sci. PubMed Scopus Google such an is to be by external including the of of RNAi-based products the from such that of RNAi-based control to pesticides policy needs towards sustainability, an of et PubMed Scopus Google and a widely in a for the of pesticides been as risk with effects of pesticides et risk and of and a review of the Scopus Google Scholar]. It is to include the of and to also that are to make to new of pesticides. be the in of RNAi-based other such as the to the application is to be or or N. et risk and with different of a of and of of PubMed Scopus Google Scholar]. it is of to develop with to ensure that and are on in the development process of RNAi-based control the of towards RNAi-based control a of the is et and change towards to food Sci. PubMed Scopus Google such an is to be by external including the of of RNAi-based products the from such that of RNAi-based control and Future sequence-specific mode of action of RNAi-based products unique in selectivity and compared with other and suggests as a to contentious pesticides or reduce in However, to to RNAi-based several to be The of and RNAi-based products in with under the and by the greater and of Furthermore, an in the of sustainable products for crop protection. The sequence-specific mode of action of RNAi-based products unique in selectivity and compared with other and suggests as a to contentious pesticides or reduce in However, to to RNAi-based several to be The of and RNAi-based products in with under the and by the greater and of Furthermore, an in the of sustainable products for crop protection. This is from by (European in and from the national and from the of and the and from the of and Food and from the Union for and

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