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<front>
<journal-meta>
<journal-id journal-id-type="publisher-id">Front. Plant Sci.</journal-id>
<journal-title>Frontiers in Plant Science</journal-title>
<abbrev-journal-title abbrev-type="pubmed">Front. Plant Sci.</abbrev-journal-title>
<issn pub-type="epub">1664-462X</issn>
<publisher>
<publisher-name>Frontiers Media S.A.</publisher-name>
</publisher>
</journal-meta>
<article-meta>
<article-id pub-id-type="doi">10.3389/fpls.2023.1137598</article-id>
<article-categories>
<subj-group subj-group-type="heading">
<subject>Plant Science</subject>
<subj-group>
<subject>Opinion</subject>
</subj-group>
</subj-group>
</article-categories>
<title-group>
<article-title>Will genetically modified late blight resistant potatoes be the first GM crops to be approved for commercial growing in Norway?</article-title>
</title-group>
<contrib-group>
<contrib contrib-type="author">
<name>
<surname>Forbes</surname>
<given-names>Edward</given-names>
</name>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Wulff-Vester</surname>
<given-names>Anders Keim</given-names>
</name>
<uri xlink:href="https://loop.frontiersin.org/people/2148088"/>
</contrib>
<contrib contrib-type="author" corresp="yes">
<name>
<surname>Hvoslef-Eide</surname>
<given-names>Trine (A.K.)</given-names>
</name>
<xref ref-type="author-notes" rid="fn001">
<sup>*</sup>
</xref>
<uri xlink:href="https://loop.frontiersin.org/people/197497"/>
</contrib>
</contrib-group>
<aff id="aff1">
<institution>Department of Plant Sciences, Faculty of Biosciences, Norwegian University of Life Sciences (NMBU)</institution>, <addr-line>Aas</addr-line>, <country>Norway</country>
</aff>
<author-notes>
<fn fn-type="edited-by">
<p>Edited by: Michael George Kepler Jones, Murdoch University, Australia</p>
</fn>
<fn fn-type="edited-by">
<p>Reviewed by: Pankaj Kumar Bhowmik, National Research Council Canada (NRC), Canada</p>
</fn>
<fn fn-type="corresp" id="fn001">
<p>*Correspondence: Trine (A.K.) Hvoslef-Eide, <email xlink:href="mailto:trine.hvoslef-eide@nmbu.no">trine.hvoslef-eide@nmbu.no</email>
</p>
</fn>
<fn fn-type="other" id="fn002">
<p>This article was submitted to Plant Biotechnology, a section of the journal Frontiers in Plant Science</p>
</fn>
</author-notes>
<pub-date pub-type="epub">
<day>01</day>
<month>03</month>
<year>2023</year>
</pub-date>
<pub-date pub-type="collection">
<year>2023</year>
</pub-date>
<volume>14</volume>
<elocation-id>1137598</elocation-id>
<history>
<date date-type="received">
<day>04</day>
<month>01</month>
<year>2023</year>
</date>
<date date-type="accepted">
<day>13</day>
<month>02</month>
<year>2023</year>
</date>
</history>
<permissions>
<copyright-statement>Copyright &#xa9; 2023 Forbes, Wulff-Vester and Hvoslef-Eide</copyright-statement>
<copyright-year>2023</copyright-year>
<copyright-holder>Forbes, Wulff-Vester and Hvoslef-Eide</copyright-holder>
<license xlink:href="http://creativecommons.org/licenses/by/4.0/">
<p>This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.</p>
</license>
</permissions>
<abstract>
<p>Last decade&#x2019;s advances in biotechnology, with the introduction of CRISPR, have challenged the regulatory framework for competent authorities all over the world. Hence, regulatory issues related to gene editing are currently high on the agenda both in the EU and in the European Economic Area (EEA) Agreement country of Norway, particularly with regards to sustainable agriculture. During the negotiations on the EEA Agreement, Norway was allowed to retain three extra aims in the Gene Technology Act: &#x201c;That the production and use of GMO happens in an ethical way, is beneficial to society and is in accordance with the principle of sustainable development&#x201d;. We argue the case that taking sustainability into the decisions on regulating gene edited products could be easier in Norway than in the EU because of these extra aims. Late blight is our chosen example, as a devastating disease in potato that is controlled in Norway primarily by high levels of fungicide use. Also, many of these fungicides are being banned due to negative environmental and health effects. The costs of controlling late blight in Norway were calculated in 2006, and since then there have been new cultivars developed, inflation and an outbreak of war in Europe increasing farm input costs. A genetically modified (GM) cisgenic late blight resistant (LBR) potato presents a possible solution that could reduce fungicide use, but this could still be controversial. This paper aims to discuss the advantages and disadvantages of approving the commercial use of a GM LBR potato cultivar in Norway and compare these against currently used late blight management methods and conventional potato resistance breeding. We argue that a possible route for future regulatory framework could build upon the proposal by the Norwegian Biotechnology Advisory Board from 2019, also taking sustainability goals into account. This could favour a positive response from the Competent Authorities without breeching the European Economic Area (EEA) Agreement. Perhaps the EU could adopt a similar approach to fulfil their obligations towards a more sustainable agriculture?</p>
</abstract>
<kwd-group>
<kwd>
<italic>Solanum tuberosum</italic>
</kwd>
<kwd>
<italic>Phytophora infestans</italic> resistance</kwd>
<kwd>financial impact</kwd>
<kwd>regulatory framework</kwd>
<kwd>sustainability</kwd>
<kwd>preparedness</kwd>
<kwd>CRISPR</kwd>
<kwd>Norwegian Gene Technology Act</kwd>
</kwd-group>
<contract-sponsor id="cn001">Norges Forskningsr&#xe5;d<named-content content-type="fundref-id">10.13039/501100005416</named-content>
</contract-sponsor>
<counts>
<fig-count count="0"/>
<table-count count="0"/>
<equation-count count="0"/>
<ref-count count="44"/>
<page-count count="5"/>
<word-count count="2042"/>
</counts>
</article-meta>
</front>
<body>
<sec id="s1">
<label>1</label>
<title>Background</title>
<p>Today, most nations face food security as being vulnerable, and Norway is potentially the most vulnerable nation concerning food security in Europe. Only 3% of Norwegian land is used for growing food, and of that only 30% is used for grain and 1.4% for potatoes (<xref ref-type="bibr" rid="B13">Flaten and Hisano, 2007</xref>; <xref ref-type="bibr" rid="B27">Lombn&#xe6;s et&#xa0;al., 2011</xref>). Over half of the calories consumed in Norway and around 25% of potatoes are imported (<xref ref-type="bibr" rid="B38">Svennerud, 2021</xref>; <xref ref-type="bibr" rid="B3">Angelsen and Rebnes, 2022</xref>), making Norway highly dependent on the global food supply chain. In the event of a global food crisis, such as drought, war or a severe pandemic, major food exporting countries may significantly reduce export of basic food products, as we saw recently with Ukraine after the Russian invasion (<xref ref-type="bibr" rid="B17">Glauben et&#xa0;al., 2022</xref>), and in severe cases Norway could struggle to feed its population.</p>
<p>Potatoes are the fourth most important crop in the world after corn, rice and wheat, and they are an important source of nutrition both globally and in Norway (<xref ref-type="bibr" rid="B27">Lombn&#xe6;s et&#xa0;al., 2011</xref>). The potato plays an important role in sustainably maintaining Norwegian food security, especially under a crisis scenario (<xref ref-type="bibr" rid="B13">Flaten and Hisano, 2007</xref>), as potato production is more land and fertiliser efficient per hectare than grain production, potatoes can be produced over the whole of Norway, and tubers are full of important minerals and vitamins and can be stored for long periods of time (<xref ref-type="bibr" rid="B8">Devaux et&#xa0;al., 2014</xref>; <xref ref-type="bibr" rid="B36">Store Norske Leksikon, 2021</xref>).</p>
<p>The oomycete pathogen <italic>Phytophtora infestans</italic> causes the disease late blight in potato, that threatens potato harvests globally (<xref ref-type="bibr" rid="B19">Hijmans et&#xa0;al., 2000</xref>). It is the most significant potato disease in Norway (<xref ref-type="bibr" rid="B33">S&#xe6;thre et&#xa0;al., 2006</xref>), resulting in high levels of fungicide application with negative effects on human health and the environment. It produces zoospores and sporangia that can travel large distances, as well as overwintering oospores that can survive in soils up to 5 years and act as primary inoculum, making crop rotation as a control less effective (<xref ref-type="bibr" rid="B33">S&#xe6;thre et&#xa0;al., 2006</xref>). With wetter summers and warmer winters, the effects of climate change in Norway are expected to create more favourable conditions for the spread and infectiousness of <italic>P. infestans</italic> on potato (<xref ref-type="bibr" rid="B7">Cooke et&#xa0;al., 2011</xref>).</p>
<p>In 2006, late blight in potato was estimated to cost 55-65 million NOK annually, with fungicides costing farmers on average 22.9 million NOK, application costs 25.6 million NOK, yield losses 5 to 14 million NOK and inspection, research, and advisory services 3.3 million NOK annually (<xref ref-type="bibr" rid="B33">S&#xe6;thre et&#xa0;al., 2006</xref>). We have recalculated the cost of late blight in Norway to be 105 million NOK before the Ukraine war in 2021, and 125 million NOK after in 2022, considering increased input prices due to inflation and the Ukraine war, as well as the use of modern cultivars, and including VAT of 25% (<xref ref-type="supplementary-material" rid="SM1">
<bold>Supplementary Table&#xa0;1</bold>
</xref>). In addition to this, there can be yield losses from late blight, though these are harder to calculate.</p>
<p>Several popular Norwegian potato varieties, such as &#x2018;Mandel&#x2019;, are heavily susceptible to late blight, so can only be grown at high altitudes and in Northern Norway where conditions are too harsh for late blight to survive (<xref ref-type="bibr" rid="B32">Roer, 1987</xref>; <xref ref-type="bibr" rid="B33">S&#xe6;thre et&#xa0;al., 2006</xref>). Many of these varieties contain desired traits and have commercial value, so by creating resistant cultivars, they could also be grown in low lying areas with less use of fungicides and with better soil conditions (H A Krogsti, personal conversation, 14 Mar 2022).</p>
<p>Genetic modification (GM) and gene editing (GEd) methods have both been proposed as methods of developing new late blight resistant (LBR) potato cultivars, with an estimated potential to reduce fungicide inputs by over 80% (<xref ref-type="bibr" rid="B22">Kessel et&#xa0;al., 2018</xref>). However, the use of GM technology in agriculture is highly controversial in Europe, while China has recently approved another eight new GM crops (<xref ref-type="bibr" rid="B21">ISAAA, 2023</xref>).</p>
</sec>
<sec id="s2">
<label>2</label>
<title>Current control methods for <italic>Phytophtora infestans</italic>
</title>
<p>Norwegian potato fields were sprayed with fungicide on average 5.6 times a year before 2006 (<xref ref-type="bibr" rid="B33">S&#xe6;thre et&#xa0;al., 2006</xref>). However, in recent years, this has increased to 8-9 times in a year of heavy infections, even up to 16 times a year, due to more aggressive <italic>P. infestans</italic> strains (B Glorvigen, personal conversation, 15<sup>th</sup> October 2022). Using fungicides can have severe negative economic, environmental and health effects. Controlling late blight in potatoes can be as much as 25% to 30% of Norway&#x2019;s entire fungicide usage. Hence, these effects are significant (M Alsheikh, personal conversation, 4th April, 2022). For example, the commonly used fungicide ingredient cymoxanil is suspected to cause birth defects, may cause organ damage over long-term exposure, and is moderately toxic to mammals, honeybees, aquatic organisms and earthworms (<xref ref-type="bibr" rid="B26">Lewis et&#xa0;al., 2016</xref>; <xref ref-type="bibr" rid="B30">Plantevernguiden, 2020</xref>). Zorvec-Endavia contains the bioactive compound Benthiavalicarb isopentenyl, which has shown carcinogenic potential in two different species (<xref ref-type="bibr" rid="B1">Alvarez et al., 2021</xref>). All fungicides used for late blight control have the warning symbol for toxic aquatic effects with long lasting effects (<xref ref-type="bibr" rid="B30">Plantevernguiden, 2020</xref>).</p>
<p>Because of these concerns, former common effective fungicides have been banned by the EU and therefore also in Norway (<xref ref-type="bibr" rid="B12">EU regulation, 2020</xref>; <xref ref-type="bibr" rid="B34">Saha et&#xa0;al., 2022</xref>). As more data is collected on the harmful environmental and health effects of fungicides, pressure is increasing on the EU to continue to ban fungicides, potentially threatening farmer&#x2019;s ability to chemically control late blight in the EU and Norway (<xref ref-type="bibr" rid="B12">European Regualtion, 2020</xref>; <xref ref-type="bibr" rid="B14">Forbond, 2021</xref>).</p>
<p>
<italic>P. infestans</italic> is notorious for its large genetic variation and ability to constantly mutate and develop resistance to fungicides due to an ability for both asexual and sexual reproduction (<xref ref-type="bibr" rid="B18">Haverkort et&#xa0;al., 2016</xref>). Strains with resistance to some fungicide active compounds such as propamocarb, have been found (<xref ref-type="bibr" rid="B25">Lehtinen et&#xa0;al., 2007</xref>). In our increasingly globalised world, these mutations spread quickly, making fungicide resistance to <italic>P. infestans</italic> a growing threat to potato production globally.</p>
<p>Plant breeding for LBR is a potential way of reducing need for fungicides against late blight. However, it has many challenges due to the potato&#x2019;s complex genome, that the potato reproduces primarily by vegetative reproduction making it difficult to cross, and that there is low genetic diversity (<xref ref-type="bibr" rid="B15">G&#xe1;lvez et&#xa0;al., 2017</xref>). Potato is also very susceptible to inbreeding depression (<xref ref-type="bibr" rid="B43">Zhang et&#xa0;al., 2019</xref>). Introgression of resistance genes without unwanted effects on the potato genome is difficult due to linkage drag, in addition to the fact that potato is tetraploid, whereas many of its wild relatives containing resistance genes are diploid. Some highly resistant varieties resulting from conventional plant breeding such as &#x2018;Sarpo Mira&#x2019; do exist, however these are poorly suited to the Norwegian market and growing conditions (<xref ref-type="bibr" rid="B24">Kim et&#xa0;al., 2012</xref>; <xref ref-type="bibr" rid="B16">Gillund et&#xa0;al., 2016</xref>; <xref ref-type="bibr" rid="B6">Colon et&#xa0;al., 1995</xref>).</p>
</sec>
<sec id="s3">
<label>3</label>
<title>Genetic modification for late blight resistance</title>
<p>Genetic modification presents an alternative to plant breeding without many of the abovementioned issues. Resistance (R) genes from other potato cultivars and wild relatives has to have inserted using traditional GM techniques (<xref ref-type="bibr" rid="B44">Zhu et&#xa0;al., 2012</xref>; <xref ref-type="bibr" rid="B42">Witek et&#xa0;al., 2016</xref>). In addition, it has been demonstrated that silencing certain susceptibility (S) genes for late blight can increase resistance, however more field trials are necessary to further determine how S gene silencing could affect other crop traits (<xref ref-type="bibr" rid="B37">Sun et&#xa0;al., 2016</xref>; <xref ref-type="bibr" rid="B23">Kieu et&#xa0;al., 2021</xref>). Multiple R and silenced S genes can be &#x2018;stacked&#x2019; in a cultivar to increase the strength and long-term viability of resistance to the pathogen, known as pyramiding (<xref ref-type="bibr" rid="B24">Kim et&#xa0;al., 2012</xref>; <xref ref-type="bibr" rid="B35">Sliwka et&#xa0;al., 2012</xref>).</p>
<p>One concern regarding GM crops is that introduced genes will escape to wild relatives and have negative ecosystem effects (<xref ref-type="bibr" rid="B31">Quist, 2007</xref>). However, <italic>S. tuberosum</italic> is not sexually compatible with either of the two common <italic>Solanum</italic> wild relative species that grow in western Europe: black nightshade (<italic>S.nigrum</italic>) and bittersweet (<italic>S. dulcamara</italic>). This has been demonstrated in studies by <xref ref-type="bibr" rid="B10">Eijlander and Stiekema (1994)</xref> and <xref ref-type="bibr" rid="B28">McPartlan and Dale (1994)</xref>.</p>
<p>Another concern is that cisgenes could spread to other potato growing areas. However, regulations on physical distance and growing intervals between GM and non-GM potato crops and disinfection of machinery can significantly reduce this risk (<xref ref-type="bibr" rid="B41">VKM, 2006</xref>; <xref ref-type="bibr" rid="B2">Anastassiadou et&#xa0;al., 2020</xref>).</p>
</sec>
<sec id="s4">
<label>4</label>
<title>GM terms and the regulatory framework</title>
<p>The EU defines a GMO as an organism in which &#x201c;the method of altering genetic material is done in a way that is not natural mating and/or recombination&#x201d;, and because of this, gene edited organisms using techniques such as CRISPR are regulated as GMO by the EU (<xref ref-type="bibr" rid="B39">Turnbull et&#xa0;al., 2021</xref>). However, a proposal that GEd techniques including CRISPR could be regulated separately from GM has been suggested by the Norwegian Biotechnology Advisory Board to the Norwegian government in 2018 (<xref ref-type="bibr" rid="B39">Turnbull et&#xa0;al., 2021</xref>). A governemental Committee is currently reviewing the legislation in Norway. As Norway is a member of the European Economic Area (EEA), it follows most EU rules and regulations, and therefore the definitions of GMO as given by EU&#x2019;s Deliberate Release Directive of 2001 (<xref ref-type="bibr" rid="B11">European Directive 2001</xref>; <xref ref-type="bibr" rid="B39">Turnbull et&#xa0;al., 2021</xref>). On the other hand, Brexit has lead to a revision of the rules for deliberate release of certain GEd higher plants in England, if the traditional plant breeding techniques (e.g. mutation breeding) could have obtained the same result (<xref ref-type="bibr" rid="B40">UK Practical Law, 2022</xref>).</p>
<p>Therefore, following the discovery and use of new breeding techniques (NBTs) including gene editing techniques, there is now a degree of uncertainty regarding what should be legally defined as GMO and if other classifications are necessary (<xref ref-type="bibr" rid="B9">Eckerstorfer et&#xa0;al., 2019</xref>). Gene editing is a novel technique involving site directed nucleases (SDN) to make precise incisions or insert DNA sequences at the target DNA area (<xref ref-type="bibr" rid="B39">Turnbull et&#xa0;al., 2021</xref>).</p>
<p>In Norway, the use of GM or GEd methods such as CRISPR in agriculture is essentially limited to research use and no GM food crops are grown commercially (<xref ref-type="bibr" rid="B39">Turnbull et&#xa0;al., 2021</xref>). However, this may be subject to change as political and consumer pressure to sustainably increase crop yields and adapt to climate change grows, while scientific understanding of gene technologies and their implications advances rapidly (<xref ref-type="bibr" rid="B20">Hjelkrem et&#xa0;al., 2021</xref>; <xref ref-type="bibr" rid="B39">Turnbull et&#xa0;al., 2021</xref>).</p>
<p>The three additional aims of the <xref ref-type="bibr" rid="B29">Norwegian Gene Technology Act (Norwegian Government, 1993)</xref>: &#x201c;That the production and use of GMO happens in an ethical way, is beneficial to society and is in accordance with the principle of sustainable development&#x201d;, make Norway one of the most restrictive countries in the world for approval of GM crops. However, by demonstrating that the potential GM crop can satisfy all these points, it is more likely that consumers, farmers and industry will support the decision. With the example of the LBR GM potato, this was shown in a workshop by <xref ref-type="bibr" rid="B16">Gillund et&#xa0;al. (2016)</xref>, and a study by  <xref ref-type="bibr" rid="B5">Bioteknologir&#xe5;det (2020)</xref> that showed over 70% of respondents being positive about GM if it would reduce fungicide use and yield losses and thus make agriculture more sustainable.</p>
</sec>
<sec id="s5" sec-type="conclusion">
<label>5</label>
<title>Conclusion</title>
<p>In conclusion, there is a strong case for that a LBR GM potato could be the first GM crop to be approved for commercial growing in Norway. Increasing resistance to fungicides, the banning of fungicides by the EU (and Norway), climate change and an increasing focus on Norwegian food self-sufficiency, all create urgent demand for potato cultivars with long lasting and significant LBR. GM and GEd techniques can be used to create potatoes with high levels of LBR in relatively short timeframes that would not otherwise be possible through conventional plant breeding, and therefore present an important potential tool in maintaining food security in Norway in an uncertain future.</p>
<p>It is important that the decision for GM LBR approval in Norway is made based on rational arguments and scientific understanding of its consequences, weighed against the disadvantages of the current control methods and the limitations of potato breeding, and the Norwegian three-part approval system is arguably well adapted to this. Measures can be taken to mitigate the concerns of a GM LBR potato, and arguably the risks of continuing to not use GM in Norway outweighs the risks of allowing it.</p>
</sec>
<sec id="s6" sec-type="author-contributions">
<title>Author contributions</title>
<p>The first author (EF) has done the calculations, under the guidance of the second (AW-V) and the third author (TH-E). All authors contributed to the article and to the writing, and approved the submitted version.</p>
</sec>
</body>
<back>
<sec id="s7" sec-type="funding-information">
<title>Funding</title>
<p>This work was supported by The Research Council of Norway (NRC) through the GENEinnovate project (Project # 281928).</p>
</sec>
<ack>
<title>Acknowledgments</title>
<p>We would like to thank H&#xe5;vard Eikemo, Hans Arne Krogsti, Jon Arne Dieseth, Muath Alsheikh, Magnus Mo and Borghild Glorvigen for their valuable input into the background and calculations for this paper.</p>
</ack>
<sec id="s8" sec-type="COI-statement">
<title>Conflict of interest</title>
<p>The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.</p>
</sec>
<sec id="s9" sec-type="disclaimer">
<title>Publisher&#x2019;s note</title>
<p>All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.</p>
</sec>
<sec id="s10" sec-type="supplementary-material">
<title>Supplementary material</title>
<p>The Supplementary Material for this article can be found online at: <ext-link ext-link-type="uri" xlink:href="https://www.frontiersin.org/articles/10.3389/fpls.2023.1137598/full#supplementary-material">https://www.frontiersin.org/articles/10.3389/fpls.2023.1137598/full#supplementary-material</ext-link>
</p>
<supplementary-material xlink:href="DataSheet_1.pdf" id="SM1" mimetype="application/pdf"/>
</sec>
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