Gene Editing Myths and Reality

Home , CRISPR gene editing

GENE EDITING MYTHS AND REALITY

A guide through the smokescreen CONTENTS

Introduction 05

Summary 06-09

1. Gene editing is genetic engineering, 10-14 not breeding

2. Gene editing is not precise and causes 15-20 unpredictable genetic errors

3. Gene editing causes genetic changes that 21-24 are different from those that happen in nature

4. Gene editing is risky and its products can 25-35 be unsafe

5. Gene-edited products are detectable 36-40

6. Gene-editing technology is owned and 41-48 controlled by big corporations

7. Gene editing is not a fast or reliable route 50-53 to desired outcomes

8. Gene editing is a risky and expensive 54-62 distraction from proven successful solutions to food and farming problems

Conclusion 63

Written by Claire Robinson, MPhil Editor, GMWatch.org Technical advisor: Dr Michael Antoniou Editing by Franziska Achterberg INTRODUCTION

An unprecedented drive is under way to promote new genetic modification techniques that are collectively termed gene editing – most notably CRISPR/Cas. The agricultural biotech industry claims that these techniques can provide solutions to our food and farming problems, including the challenges posed by climate change, pests, and diseases.

This guide looks at the claims and shows them to be at best misleading and at worst deceptive. Each of the eight chapters focuses on one claim about gene editing and presents the evidence proving it to be false.

In the EU, all of the claims are brought with the intention of questioning the existing GMO regulations and getting GMOs engineered with gene editing excluded from them. These regulations exist in order to protect public health and the environment and to give consumers and farmers the right to know what they are eating and planting in their fields.

It is worth noting that those who want to exclude gene editing from the GMO regulations also question those regulations as they apply to older-style GMOs. They say GMOs are beneficial and safe, and cast doubt on the need for safety assessments and labelling.

However, to exempt gene editing from the GMO regulations – or to dismantle the regulations for all GMOs – would be a step backwards and a dangerous weakening of EU health and environmental standards. This is because many of the risks attached to older-style GMOs still apply to gene-edited GMOs, and they also present new and special risks.

This guide focuses mainly on gene editing in plants because this is the area that has caught the imagination of GMO developers, researchers, and the media worldwide, though some information on livestock gene editing is also included.

It shows that gene editing is a costly and potentially dangerous distraction from the real solutions to the challenges faced by our food and farming sectors. These are mentioned throughout and form a major focus of the final chapter.

5 untested and unlabelled, and farmers and effects of the gene editing. But the cattle were food producers – including those operating revealed by US regulators to contain bacterial under organic systems – would have no way of DNA and foreign genes that confer resistance avoiding them. to antibiotics.

The misrepresentation begins with the Also, CRISPR gene editing of rice plants was Summary terminology used to describe them. Contrary shown to cause a wide range of unintended to industry claims, gene- mutations, both at the editing techniques are not Gene editing intended editing site and at The agricultural biotech industry and affiliated breeding techniques, but other locations in the genome. groups are promoting the use of new genetic are genetic modification causes many modification techniques known as techniques that share some of The researchers who made gene editing in food and farming. the same methods as old-style unintended this discovery warned that The main technique that has genetic modification. changes and CRISPR gene editing ”may caught the imagination of the be not as precise as expected industry and its supporters Also contrary to the claims genetic errors in rice”. They added, ”early is the CRISPR/Cas gene made, these techniques are and accurate molecular editing technique. not precise or controlled, nor do they have characterization and screening must be carried predictable outcomes. out for generations before transitioning The industry is using gene In addition to the intended genetic change, of CRISPR/Cas9 system from lab to field” editing to manipulate the gene editing causes many unintended changes – something that is not generally done by genomes of crop plants and and genetic errors. This can include the developers. livestock animals, in order inadvertent addition of foreign DNA from to confer new traits. other species, or even entire foreign genes, They make a range into the genome of gene-edited organisms, of claims for these even when the intention is specifically techniques – for to avoid this. example, that gene editing is precise, The effects of these changes on the safe, and so highly controlled composition of gene-edited crops, that it only gives rise to foods, and animals, as well as the predictable outcomes. They consequences to health and the environment, also say that gene editing have not been investigated and remain is widely accessible and unknown. In food crops, they could include quicker than conventional the production of unexpected toxins and breeding, and that it gives us allergens, or altered levels of existing toxins the tools to enable us The claims are being and allergens. to meet the challenges used to argue for these The industry says that the changes made by of environmental techniques to be exempted from gene editing in crops and livestock animals are degradation and climate change. the EU’s GMO regulations. This would mean small and the same as could happen in nature. that products of these techniques would not But this claim is proven false by the However, none of these claims stand up to be subjected to safety testing, traceability, worrying surprises that have already come scrutiny, as shown by the evidence presented or GMO labeling, and EU countries could to light. For example, the company that in this guide. All are exposed as false or not ban their cultivation. As a result, these developed gene-edited hornless cattle misleading. GMOs would end up on our fields and plates claimed they were free from unintended

6 7 evaluation and research licences can be obtained cheaply or free of charge, commercial licences and associated royalty payments on product sales will remain too expensive for anyone apart from large multinationals. Gene-edited products are also patented: in Given the inherent crop plants, patents cover seeds, plants, and inaccuracy of gene-editing techniques and the often the harvest, raising issues of consolidated challenges of producing gene-edited plants or control of the food supply, farmers’ autonomy, animals that perform as expected, claims that and loss of food sovereignty. gene editing can produce useful traits far more Conventional breeding, in contrast, continues Gene editing is a costly distraction from these quickly than conventional breeding are highly A form of emotional blackmail is being to be highly successful in achieving such traits systems-based solutions. Its exclusion from questionable. Even if the time taken to gain used to convince policymakers of the moral and far outstrips GM approaches. EU GMO regulations would serve to boost regulatory approval is imperative to embrace a questionable experiment with unknown excluded, it is unlikely new GM technologies. It is not enough to consequences for A form of emotional focus on genetics people, animals and that the time needed to The promise is that these Gene editing is a costly commercialize gene- blackmail is being technologies will enable as the solution the environment. It edited crops will be the development of crops to agricultural distraction from real, would also deprive significantly shorter used to convince that require less pesticide problems – whole European consumers, than with conventional and are adapted to climate systems approaches systems-based solutions farmers and breeders breeding. Moreover, policymakers of the change. are needed. This of the right to know achieving useful traits moral imperative to would entail a large- where these GMOs are in crops or animals However, the same scale shift to proven-successful agroecological and impede advances in non-GM approaches, is not just a matter of embrace new GM promises were also made systems of farming, which include low-input, including organic and agroecological systems. speed – it is a question technologies for first-generation GM genuinely sustainable, and regenerative It would represent a significant weakening of of using the best tools crops and proved false. methods. These methods are already available EU health and environmental protections for the job, and GM New GM techniques are and only need to be properly supported to and undermine the rollout of proven approaches are not an efficient route. unlikely to succeed where “old GM” failed, enable broader rollout effective and sustainable solutions to because desirable traits such as pest and disease our food and farming challenges. Despite years of research and permissive resistance and adaptation to climatic changes regulatory regimes in some countries, only are genetically complex traits that cannot be two gene-edited products have successfully achieved by manipulating one or a few genes. made it to market and neither was produced with the much-hyped CRISPR/Cas tool.

The claim that gene editing, in particular through CRISPR/Cas, will make agricultural innovation accessible to publicly funded breeding programmes is disproven by the fact that the technology is already owned and controlled by a very few large corporations, led by Corteva and Monsanto/Bayer. While

8 9 European institutions also avoid the terms 1. Gene editing is “genetic modification” and “GMO”. The Council of Ministers introduced the term “novel genomic techniques”,6 which the genetic engineering, Commission adapted to “new genomic techniques”.7 The Commission also talks about not breeding “new techniques in biotechnology”.8 The use of the term “breeding” appears to be an attempt to give an air of naturalness to the new genetic engineering techniques and thus convince the public to accept them. It may also be an attempt to make the application of GMO regulations appear counterintuitive MYTH and illogical: If gene-edited products are not GMOs, why should they be regulated as Gene-editing techniques are REALITY GMOs? “new breeding techniques’’, However, gene-editing techniques are not “precision breeding’’ or Technically and legally, breeding techniques. They are technically and gene-editing techniques legally GM techniques, give rise to genetically “breeding innovation’’. modified organisms (GMOs), and fall within genome. In contrast, the terms “mating and/ are genetic modification the scope of EU GMO laws, as confirmed by or natural recombination” describe natural techniques, not the European Court processes used in of Justice ruling of conventional plant and breeding methods. 2018.9,10 EU law defines animal breeding. a GMO as an organism EU law defines a EU GMO law exempts GMO as an organism in which “the genetic some GMOs, such as in which “the genetic those produced using a material has been material has been decades-old technique altered in a way called mutation that does not occur altered in a way breeding (also called naturally by mating The agricultural biotechnology industry that does not occur random mutagenesis), and/or natural and its lobbyists often refer to new genetic from its requirements recombination’’.11 This naturally by mating modification (GM) techniques, especially for authorisation, wording accurately gene editing, as “breeding innovation”, traceability and describes the way and/or natural “precision breeding techniques” and “new labelling. But this is in which older- breeding techniques”.1,2,3,4 They strenuously recombination’’ only possible if they style transgenic and try to avoid the terms “genetic modification” were produced using new GMOs, such as and “genetic engineering”. Corteva, the techniques that have a “long safety record”.9 gene-edited plants, are produced. Genetic company that controls the use of CRISPR This is clearly not the case with gene editing. modification employs artificial techniques gene editing in crop plants, even argues that that require direct human intervention in the “CRISPR-produced plants are not GMOs”.5

10 11 14 HOW DOES GENE Some divide SDN procedures into SDN-1, SDN-2, and SDN-3. They can be defined as follows: • SDN-1 refers to disruption • SDN-2 refers to gene • SDN-3 refers to gene EDITING WORK? of the function of a gene (also alteration. While the break is insertion. The DNA break is known as gene knockout). repaired by the cell, a repair accompanied by a template Old and new GMOs have more in common repair process to mend the double-strand The repair of the double- template is supplied that is containing a gene or other than proponents would have us believe. Of DNA cut. While the initial break in the DNA strand break in the DNA complementary to the area sequence of genetic material. three steps involved in genome editing – can be targeted to a specific site in the genome, results in either a deletion of the break, which the cell The cell’s natural repair gene delivery, gene editing, and whole plant the subsequent “repair” is carried out by the (removal) of part of the gene uses to repair the break. process uses this template to regeneration in tissue culture – the first and cell’s innate repair mechanisms and cannot or the insertion of additional The template contains one repair the break, resulting in last essentially re- be controlled by the DNA base units, which are or several DNA base unit the insertion of new genetic main the same. The genetic engineer.’ taken from the genome of the sequence changes in the material (foreign DNA, which first step, delivery of While the initial break organism that is being edited. genetic code, which the repair can include a whole new gene). This disrupts the sequence of mechanism exchanges into The aim is to confer novel foreign genetic ma- The repair is often in the DNA can be the gene and thus knocks out the plant’s genetic material, functions and characteristics terial into the plant not clean or precise, its normal function. resulting in a mutation of the on the organism. cells (also called targeted to a specific but can result in target gene. The mutated gene GM transforma- “chromosomal may- will then produce an altered tion) is usually done site in the genome, the hem” in the genome, protein product with an with the help of to cite the title of subsequent “repair’’ altered function. small circular DNA a commentary on molecules (plasmids) cannot be controlled studies on CRISPR/ that are introduced Cas gene editing in into the cells using by the genetic engineer human embryos.13 a soil bacterium Another gene-editing technique is oligonucleotide-directed mutagenesis (ODM). ODM does called Agrobacterium tumefaciens or a not cause a double-strand break in the DNA. Instead it involves the introduction of short The result of the repair is called the “edit”. method called particle bombardment. The sequences of synthetic DNA and RNA – called oligonucleotides – into the cells. The oligo- Researchers must select from many edited plasmid then inserts itself into the plant nucleotide interacts with the cell’s DNA, tricking the cell’s repair mechanisms into altering organisms to obtain the one they desire.12 cell’s DNA. the cell’s own DNA to match that of the oligonucleotide.

Regarding the “editing step’’, the majority of All these techniques will change the biochemistry of the plant – this is the aim of gene editing – so that a new trait can result. gene-editing applications involve first cutting the DNA with enzymes, called nucleases, which are supposed to act only at chosen sites in the genome of a living cell.

These gene-editing applications are called “site-directed nuclease” or “SDN” procedures. The SDN creates a double-strand break in the DNA. The enzymes most commonly used for this cutting are the Cas GENE EDITING IS family of proteins (for CRISPR) and FokI (for TALENs and Zinc Finger Nucleases).12 GENETIC MODIFICATION The cutting event triggers alarm signals in the cell, as broken DNA is dangerous to Although GM and conventional breeding will result in the creation of new varieties, the two the organism. So the cell initiates a DNA are distinct methods and are not interchangeable. Gene editing is clearly a GM technique but conventional breeding is not, however hard the agricultural biotech industry tries to blur the boundaries.

12 13 REFERENCES 2. Gene editing

1. Euroseeds. Plant breeding innovation. Euroseeds.eu. Pub- 9. European Court of Justice. C-528/16 - Confédération Pay- lished 2020. Accessed December 8, 2020. https://www.euroseeds. sanne and Others: Judgement of the Court.(European Court of eu/subjects/plant-breeding-innovation/ Justice 2018). Accessed September 27, 2019. http://curia.europa. is not precise and eu/juris/documents.jsf?num=C-528/16 2. International Seed Federation. Technological advances drive innovation in plant breeding to create new variet- 10. European Court of Justice. Press release: Organisms ies. worldseed.org. Published 2020. Accessed December 8, obtained by mutagenesis are GMOs and are, in principle, sub- causes unpredictable 2020. https://www.worldseed.org/our-work/plant-breeding/ ject to the obligations laid down by the GMO Directive. Judg- plant-breeding-innovation/ ment in Case C-528/16 Confédération paysanne and Others v Premier ministre and Ministre de l’Agriculture, de l’Agroali- 3. Von Essen G. Precision breeding – smart rules for new tech- mentaire et de la Forêt. Published online July 25, 2018. https:// genetic errors niques! european-biotechnology.com. Published 2020. Accessed curia.europa.eu/jcms/upload/docs/application/pdf/2018-07/ December 8, 2020. https://european-biotechnology.com/people/ cp180111en.pdf people/precision-breeding-smart-rules-for-new-techniques. html 11. European Parliament and Council. Directive 2001/18/EC of the European Parliament and of the Council of 12 March 2001 4. NBT Platform. New Breeding Techniques Platform. nbt- on the deliberate release into the environment of genetically platform.org. Published 2015. Accessed January 8, 2021. https:// modified organisms and repealing Council Directive 90/220/ www.nbtplatform.org/ EEC. Official Journal L. 2001;106:1-39. http://eur-lex.europa.eu/ legal-content/en/TXT/?uri=CELEX%3A32001L0018 MYTH 5. Corteva Agriscience. CRISPR Q&A – For internal use only. Published online May 28, 2019. https://crispr.corteva.com/ 12. Latham J. Gene-editing unintentionally adds bovine REALITY wp-content/uploads/2019/05/FINAL_For-Internal-Use-On- DNA, goat DNA, and bacterial DNA, mouse researchers find. Gene-editing tools such as ly_Corteva-CRISPR-QA-UPDATED-5.28.19.pdf Independent Science News. https://www.independentsciencenews.org/health/gene-editing-unintentionally-adds-bo- 6. European Council. Council Decision (EU) 2019/1904 of 8 CRISPR/Cas bring about vine-dna-goat-dna-and-bacterial-dna-mouse-research- Gene editing is not November 2019 Requesting the Commission to Submit a Study ers-find/. Published September 23, 2019. in Light of the Court of Justice’s Judgment in Case C-528/16 changes in the genome in a precise, but causes many Regarding the Status of Novel Genomic Techniques under 13. Ledford H. CRISPR gene editing in human embryos Union Law, and a Proposal, If Appropriate in View of the Out- wreaks chromosomal mayhem. Nature. 2020;583(7814):17-18. precise and controlled way, genetic errors, with comes of the Study. Vol 293; 2019. Accessed December 18, 2020. doi:10.1038/d41586-020-01906-4 http://data.europa.eu/eli/dec/2019/1904/oj/eng with predictable outcomes. 14. NBT Platform. SDN: Site-Directed Nuclease Tech- unpredictable results, 7. European Commission. EC study on new genomic technology. NBT Platform; 2014. https://www.google.com/ niques. Food Safety - European Commission. Published Jan- url?sa=t&rct=j&q=&esrc=s&source=web&cd=&ved=2a- in addition to any uary 23, 2020. Accessed March 20, 2020. https://ec.europa.eu/ hUKEwjmpuf02YfuAhUyQkEAHR3fC84QFjAAegQIA- food/plant/gmo/modern_biotech/new-genomic-techniques_en hAC&url=https%3A%2F%2Fwww.nbtplatform.org%2Fback- intended genetic ground-documents%2Ffactsheets%2Ffactsheet-site-directed-nu- 8. European Commission. New techniques in biotechnology. cleases.pdf&usg=AOvVaw1qCEJhVE-GXPoHC9iIhHnq ec.europa.eu. Published undated. https://ec.europa.eu/food/ change. plant/gmo/modern_biotech_en The agricultural biotech industry and its allies However, claim that gene-editing tools such as CRISPR/ these claims do Cas bring about changes in the genome in a not survive scrutiny.A 1,2,3 precise and controlled way. Some even claim large and ever-growing number of that they bring about only the specific intended scientific studies in human, animal and plant cells 4,5 changes and nothing else. They argue that show that gene editing is not precise but gives gene-edited products should therefore be rise to numerous genetic errors, also known as excluded from the regulatory oversight applied unintended mutations (DNA damage). 3,5 to older-style transgenic GMOs, where (in These occur at both off-target sites in the most cases) DNA is introduced from another genome (locations other than that targeted for species into a part of the genome that cannot be the edit) and on-target (at the desired editing determined beforehand. site). The types of mutation include large deletions, insertions, and rearrangements of DNA.6,7,8

14 15 These mutations occur at various stages of DNA of plant cells).9 A study on rice varieties found that CRISPR a genetically complex trait that involves the the process, including stages that gene editing gene editing caused a wide range of undesirable functioning of many, if not all, gene families has in common with old-style transgenic Even the intended changes can cause and unintended on-target and off-target of the plant. Thus altering the function of one GM methods, such as tissue culture and GM unintended effects (“pleiotropic effects”) mutations. The gene to improve transformation by Agrobacterium tumefaciens in the edited organism,10 since genes and researchers yield could be infection (in which this soil bacterium is used their protein or RNA products act in were aiming In plants, alterations in the viewed as a futile to insert the foreign genetic material into the networks and not in isolation. to improve the pattern of gene function exercise. yield of already high-performing can lead to compositional The researchers varieties of rice warned that GENE EDITING PRODUCES A by disrupting changes, which could prove CRISPR gene RANGE OF UNINTENDED the function of to be toxic and/or allergenic editing “may be a specific gene, not as precise MUTATIONS in an SDN-1 to human or animal as expected (gene disruption) consumers in rice“. They Even the simplest application of gene editing (so-called SDN-1), procedure.15 added, ”early which is intended to destroy a gene function, can lead to unwanted They were trying and accurate mutations.11,12,13 These mutations can lead to the creation of new to produce small insertions and deletions of molecular characterization and screening gene sequences producing new mutant proteins, with unknown DNA base units in the genome. However, what must be carried out for generations before consequences to the health of consumers of the gene-edited they got was quite different. In many cases transitioning of CRISPR/Cas9 system from lab organism. In addition, alterations in the pattern of gene they found large insertions, deletions, and to field”.15 Developers do not generally do this, function can take place rearrangements of DNA, raising the possibility or if they do, the results are not published. Unwanted within the organism that the function of genes other than the one whose genome has targeted could have been altered.15 The researchers concluded, “Understanding mutations can lead been modified. of uncertainties and risks regarding genome As for the hoped-for increased yield, the editing is necessary and critical before a new to the creation of In plants, these opposite was found – yield was reduced.15 global policy for the new biotechnology is new gene sequences alterations can lead to This should not come as a surprise, as yield is established”.15 compositional changes, producing new which, scientists warn, mutant proteins, could prove to be toxic and/or allergenic INADEQUATE SCREENING with unknown to human or animal consequences to the consumers.6,8,14 FOR UNINTENDED MUTATIONS health of consumers Unintended mutations Most studies that look for unintended use inadequate detection methods – short-range and their effects are under- mutations in gene-edited plants grossly PCR and short-read DNA sequencing – to look of the gene-edited researched in plants underestimate the number of mutations for mutations. They only look at short stretches organism compared with human resulting from gene editing and associated of the DNA around the targeted editing site and and animal cells. But processes such as tissue culture (growth of plant computer programme-predicted off-target sites. since the mechanisms tissues or cells in a growth medium). This is of gene editing and subsequent DNA repair are the same true both for studies that conclude that gene As Kosicki and colleagues found in a study between animals and plants, there is every reason to editing causes many such mutations and those on human cells, short-range PCR and short- believe that the types of unintended mutations seen in that conclude that it causes few or none. read DNA sequencing can miss major genetic human and animal cells will also be found in plants. The reason is that the authors of these studies errors, such as large deletions and insertions Recent research in rice plants attests to this fact.15

16 17 and complex rearrangements of DNA.16,17 The and the subsequent repair that forms the “edit” researchers concluded that a combination are the same. “OLD” MUTAGENIC GM TECHNIQUES of long-range PCR and long-read DNA ARE USED IN GENE EDITING sequencing is needed to spot the full range of In a scientific review, Kawall and colleagues 16 unintended mutational effects. FDA scientists confirmed that the “vast majority” of studies First-generation genetic engineering techniques the study found that the CRISPR process, taken have made the same recommendation, with on gene-edited plants used biased detection are still often used to introduce CRISPR editing as a whole, caused large numbers of off-target 18 regard to gene-edited animals. methods to screen for genetic errors, meaning tools into plant cells. Plasmids containing mutations and far more than conventional that they will miss many such errors. Among genes encoding the CRISPR/Cas editing tool breeding. This principle applies to plants just as much as studies on gene-edited animals, none included a are introduced into the cells using either 6 animals, since the mechanisms of gene editing thorough analysis of genetic errors. Agrobacterium tumefaciens infection or particle Ironically, this study is often cited as an example bombardment.6 In addition, tissue culture is of the precision of this gene-editing tool. used to grow the This is because CIBUS’S CANOLA: “PRECISION” GENE plant cells. All three A study on CRISPR gene- it found that the processes are highly CRISPR editing EDITING OR ACCIDENT IN A PETRI DISH? mutagenic.25 The edited rice has found tools themselves mutations caused did not introduce In September 2020, the biotech company Cibus to announce that the crop was not gene-edited by these processes that many off-target many off-target claimed that its herbicide-tolerant SU Canola after all. will be in addition mutations resulted from mutations into (oilseed rape) was not gene-edited but was the to the unwanted the plants’ DNA.9 result of random mutation caused by tissue It would appear that Cibus made that claim mutations caused tissue culture, and yet However, this culture – effectively, an accident in a laboratory only to evade EU GMO regulations. The timing by the gene repair more resulted from finding is likely Petri dish. This claim came after the company is remarkable: Shortly before Cibus made its process (the actual not accurate, due had for many years statement,20 a ”edit”). Agrobacterium infection to the researchers’ said (including to The vast majority of scientific paper had use of inadequate regulators) that SU been published, A study by Tang screening methods Canola was made studies on gene-edited reporting the and colleagues on CRISPR gene-edited rice (see “Inadequate screening for unintended with its “precision plants used biased development of illustrates the mutagenic nature of these mutations”, above) – they did not use long-read gene editing” the first publicly processes. The study found that many off-target DNA sequencing. Also, the findings must be technique, called detection methods to available detection mutations resulted from the tissue culture, viewed in the context of the above-mentioned oligo-directed method for SU and yet more resulted from Agrobacterium separate study on rice that found that CRISPR mutagenesis screen for genetic errors Canola.24 However, infection (around 200 per plant). In contrast, gene editing caused a wide range of unintended (ODM).19,20,21 under EU law, seed saved from non-GM rice plants had only on-target and off-target mutations.15 In fact, ODM constitutes the very foundation of even if the specific mutation that confers the 30–50 spontaneous mutations per plant.9 Thus its business model.22 herbicide tolerance was not the intended result of the ODM editing process, the fact that the Indeed, numerous public records point to the ODM tool was used to develop the SU Canola fact that Cibus used gene editing in the process means that it is a GMO. Since it has no EU THREAT TO HEALTH AND of engineering SU Canola.19,20,23 But it turned authorisation, its presence in EU imports would ENVIRONMENT out that the oligonucleotide used was designed be illegal.23 to produce a different genetic change from Based on the above evidence, gene editing is neither precise nor controllable, but could the one that was found to confer herbicide This episode raises questions about Cibus’s inadvertently produce traits that threaten public health and the environment. tolerance in SU Canola and that Cibus described honesty and transparency. But more in its patent application.21 So the “precision” importantly, it shows that the precision and tool did not work as intended, leading Cibus control claimed for the ODM gene-editing technique was false.

18 19 REFERENCES

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GMWatch.org. doi:10.1038/s41587-019-0394-6 about by gene editing Published November 20, 2019. https://www.gmwatch.org/en/ Gene editing causes genetic news/latest-news/19223 19. Achterberg F. Gene edited crop can’t stand the light are the same as could of day. Greenpeace European Unit. Published Septem- 8. Agapito-Tenfen SZ, Okoli AS, Bernstein MJ, Wikmark O-G, changes that are different ber 15, 2020. Accessed January 2, 2021. https://www. Myhr AI. Revisiting risk governance of GM plants: The need happen in nature or greenpeace.org/eu-unit/issues/nature-food/45028/ to consider new and emerging gene-editing techniques. Front from those that happen gene-edited-crop-cant-stand-the-light-of-day Plant Sci. 2018;9. doi:10.3389/fpls.2018.01874 mutation breeding. 20. Robinson C. Company claims first commercial gene-edited in nature or mutation 9. Tang X, Liu G, Zhou J, et al. A large-scale whole-genome crop wasn’t gene-edited after all. GMWatch.org. Published 21 sequencing analysis reveals highly specific genome editing by September. Accessed December 10, 2020. https://www.gmwatch. breeding and their both Cas9 and Cpf1 (Cas12a) nucleases in rice. Genome Biology. org/en/news/latest-news/19535-company-denies-first-commer- 2018;19(1):84. doi:10.1186/s13059-018-1458-5 cial-gene-edited-crop-is-gene-edited consequences are poorly 10. Eckerstorfer MF, Dolezel M, Heissenberger A, et al. An EU 21. VLOG, Ohne Gentechnik hergestellt, IFOAM, Greenpeace. perspective on biosafety considerations for plants developed GMO status of Cibus SU Canola. Published online November 9, understood. by genome editing and other new genetic modification tech- Lobbyists claim that gene editing techniques 2020. https://afec408b-c77e-4bd1-86e4-dcaa6f3e25df.filesusr.com/ niques (nGMs). Front Bioeng Biotechnol. 2019;7. doi:10.3389/ ugd/cbe602_73707414d403427faa2efe3ba1e1c83d.pdf “generally create plant products that may also fbioe.2019.00031 be obtained using earlier breeding methods”1 22. Cibus. Innovating traditional plant breeding. cibus.com. Pub- 11. Tuladhar R, Yeu Y, Piazza JT, et al. CRISPR-Cas9-based lished 2021. https://www.cibus.com/our-technology.php such as mutation breeding, or that could result mutagenesis frequently provokes on-target mRNA misregula- “from spontaneous processes in nature”.2 tion. Nat Commun. 2019;10(1):1-10. doi:10.1038/s41467-019-12028-5 23. Robinson C. Lawyer wades into row over Cibus’s gene-edited canola. GMWatch.org. Published October 25, 2020. Accessed tion breeding, yet mutation bred plants are 12. Mou H, Smith JL, Peng L, et al. CRISPR/Cas9-mediated December 10, 2020. https://www.gmwatch.org/en/news/latest- Mutation breeding (also called random exempted from the requirements of the GMO genome editing induces exon skipping by alternative splic- news/19572-lawyer-wades-into-row-over-cibus-s-gene-edited- ing or exon deletion. Genome Biology. 2017;18:108. doi:10.1186/ mutagenesis) is a decades-old technique in regulations, so gene-edited plants should also canola s13059-017-1237-8 which seeds are exposed to chemicals or be exempted.3 24. Chhalliyil P, Ilves H, Kazakov SA, Howard SJ, Johnston BH, 13. Smits AH, Ziebell F, Joberty G, et al. Biological plasticity radiation to induce mutations in the hope that Fagan J. A real-time quantitative PCR method specific for detec- rescues target activity in CRISPR knock outs. Nat Methods. tion and quantification of the first commercialized genome-ed- one or more may result in a useful trait. The However, claims that gene editing can produce 2019;16(11):1087-1093. doi:10.1038/s41592-019-0614-5 ited plant. Foods. 2020;9(9):1245. doi:10.3390/foods9091245 lobbyists say that gene editing is more precise organisms that could arise in nature or through

25. Latham JR, Wilson AK, Steinbrecher RA. The mutational than muta mutation breeding are entirely theoretical. consequences of plant transformation. J Biomed Biotechnol. 2006;2006:1-7. doi:10.1155/JBB/2006/25376

20 21 MUTATIONS FROM GENE EDITING ARE

No one has proven that any given gene-edited Indeed, if someone were to produce DIFFERENT IN TYPE FROM THOSE FROM organism is the same as a naturally occurring a gene-edited organism that was the CONVENTIONAL OR MUTATION BREEDING vor mutation bred organism, either at the level same as a naturally bred one, this of the genome or in terms of its molecular would call into question any patent Evidence shows that regulation for alterations, A separate scientific review composition (the proteins and natural chemicals on the gene-edited organism, as mutations induced by gene since the objective is to change shows that gene-editing that make up the structure and function of the patents require an “inventive step”. editing are not the same as a trait. Second, much of the techniques enable complex organism). those induced by chemicals off-target mutation-causing alterations of genomes that or radiation in mutation activity of the gene-editing would be extremely difficult breeding. For example, a tool will occur at locations or impossible to achieve with NO EVIDENCE THAT CHANGES scientific review shows that within the genome with a conventional breeding or gene editing can produce similar DNA sequence to mutation breeding. In gene FROM GENE EDITING ARE FEWER changes in areas of the genome the intended target site. This editing, so-called multiplexing THAN FROM CONVENTIONAL that are otherwise protected means that if the intended approaches allow the targeting from mutations. gene editing target site is a and alteration of multiple OR MUTATION BREEDING In other words, gene editing gene’s coding region or its gene variants, which can makes the whole genome regulatory elements, off-target be members of the same or accessible for changes.5 mutations will different gene families.6 Dr Michael Antoniou, a molecular geneticist occur in other based at a leading London university, said Dr Michael Antoniou says genes with a In summary, gene editing that claims that the mutations induced by that mutations induced by similar DNA can cause specific unintended gene editing are the same as could happen mutation breeding will more sequence. effects and can be used in nature or mutation breeding are often than not occur in to generate novel genetic scientifically unfounded. Moreover, he areas of the genome As a result, off-target combinations that cannot said there is no evidence demonstrating that are non-coding and unintended on- readily be achieved using that gene editing any studies and non-regulatory target mutations conventional breeding or is more precise, in using reliable “Gene editing can cause and therefore are are likely to mutagenesis techniques. It can the sense of causing screening methods unlikely to affect affect important overcome genetic limitations fewer mutations, large deletions, insertions, that compare the gene function. protein-coding that exist in conventional than conventional frequency of these and rearrangements in gene regions breeding.6 breeding or types of large-scale With gene editing, in and gene mutation breeding. DNA damage in DNA, which can affect the contrast, mutations regulatory These unique attributes of conventionally bred, are more likely to activity. gene-editing applications show He said “Gene function of multiple genes mutation bred, and happen at locations that they pose unique risks, editing can cause gene-edited plants. at off-target and in the genome that justifying strict regulation. large deletions, What we do know directly affect the insertions, and on-target sites’’ is that there is function of one or rearrangements in clear experimental - Dr Michael Antoniou more genes. First, there DNA, which can evidence showing is intentional targeting of affect the function of multiple genes at off- that assumptions that gene editing only causes a gene’s coding region or its target and on-target sites.” I am not aware of small insertions and deletions at off-target and regulatory elements to alter its on-target sites are false.”4 function. Gene editors will preferentially target sites that are relevant for protein production and gene

22 23 REDESIGNING NATURE

CRISPR inventor Jennifer Doudna has made However, given that scientists do not fully clear that the aim of CRISPR gene editing is not understand the function of the vast complex 4. Gene editing is risky to replicate or enhance nature but to redesign networks of genes and their products that and replace it. She wrote: constitute a healthy functioning organism, “Gone are the days when life was shaped they are not remotely close to being able to and its products can exclusively by the predict the outcome plodding forces of The limitations even of a single gene evolution. We’re manipulation. Thus it be unsafe standing on the cusp imposed by natural is difficult to see how a of a new era, one in new era in human-led which we will have processes may help, predictable, directed primary authority over rather than impede, evolution has dawned. life’s genetic makeup From this perspective, and all its vibrant and evolution when it comes to MYTH varied outputs. Indeed, evolutionary processes, we are already supplanting the deaf, dumb, and it is arguably genetic engineering that is a “deaf, The precision and control of REALITY blind system that has shaped genetic material dumb, and blind system”, rather than nature. on our planet for eons and replacing it with gene editing mean that it is The unintended a conscious, intentional system of human- The limitations imposed by natural processes safe-by-design. directed evolution.”7 outcomes of gene may help, rather than impede, evolution. editing lead to risks, NOT NATURE-IDENTICAL which are poorly

The evidence shows that the genetic changes With this in mind, gene editing must remain understood. Claims that gene editing is “breeding”, that it compared brought about by gene editing are different under the EU’s GMO regulations and the risk is “precise”, and that outcomes are “nature- to traditional from those that would happen in nature or assessment should be broadened to take account identical” are often made to imply that gene- plant breeding”.1 mutation breeding and their outcomes and the of the special risks attached to the technology. edited organisms will be safe-by-design. And Corteva says that risks attached to them are poorly understood. CRISPR-edited plants are Some GMO “as safe as plants found developers have Some GMO developers in nature or produced REFERENCES gone further, through conventional 1. Euroseeds. Position: Plant Breeding Innovation. subject gene-edited plants to strict safety assessments. explicitly claiming claim that gene-edited breeding”.2 Euroseeds; 2018. https://www.euroseeds.eu/app/ GMWatch.org. Published November 20, 2019. https:// that gene-edited uploads/2019/07/18.1010-Euroseeds-PBI-Position-1.pdf www.gmwatch.org/en/news/latest-news/19223 plants are just as safe plants are just as safe The agbiotech 2. EuropaBio. Achieving the potential of genome editing. 5. Kawall K. New possibilities on the horizon: Genome EuropaBio.org. Published June 2019. Accessed January editing makes the whole genome accessible for changes. as conventionally as conventionally industry argues that 10, 2021. https://www.europabio.org/cross-sector/ Front Plant Sci. 2019;10. doi:10.3389/fpls.2019.00525 bred ones. it would therefore be publications/achieving-potential-genome-editing bred ones 6. Kawall K, Cotter J, Then C. Broadening the GMO risk Bayer claims that “disproportionate” to 3. Askew K. CRISPR genome editing to address food assessment in the EU for genome editing technologies compared with subject these products security and climate change: “Now more than ever we in agriculture. Environmental Sciences Europe. are looking to science for solutions.” foodnavigator.com. 2020;32(1):106. doi:10.1186/s12302-020-00361-2 conventional breeding, CRISPR/Cas gene to GMO regulatory requirements aimed at Published online May 4, 2020. Accessed January 29, 2021. editing is “simpler, faster and more precise, ensuring their safety.3 Corteva sees no need to https://www.foodnavigator.com/Article/2020/05/04/ 7. Doudna JA, Sternberg SH. A Crack in Creation: Gene CRISPR-genome-editing-to-address-food-security-and- Editing and the Unthinkable Power to Control Evolution. with no impact on the safety of the final crop conduct safety testin on its gene-edited crops climate-change-Now-more-than-ever-we-are-looking- Houghton Mifflin Harcourt; 2017. to-science-for-solutions

4. Robinson C, Antoniou M. Science supports need to

24 25 and says it tests CRISPR-produced plants in Techniques common to both gene editing and “the same way” as it tests conventionally bred older transgenic GM methods, such as tissue plants.4 culture and GM transformation, will lead to additional mutations However, as Unintended genetic (see chapter 2). we have seen in previous chapters, changes will alter the These unintended gene editing is pattern of gene function genetic changes will not precise, nor alter the pattern of are the outcomes within the organism gene function within identical to those the organism. of conventional breeding. While the initial cut In plants, this can alter biochemical pathways in the DNA can be targeted to a specific region and lead to compositional changes, which, (retroviruses include cancer-causing “onco- components from animals is not used in making of the genome, the subsequent DNA repair scientists warn, could include the production of retroviruses” and human immunodeficiency gene-edited plants, so the presence of animal process causes unwanted mutations both at novel toxins and allergens or altered levels of virus, HIV, which can lead to AIDS). Thus gene DNA is not a concern. on-target and off-target sites in the genome.5,6,7 existing toxins and allergens.8,9,10 editing is a potential mechanism for horizontal gene transfer (the transfer of genetic material by However, in cases where genetic engineers any method other than “vertical” transmission deliver the gene-editing tool into plant cells of DNA from parent to offspring) of disease- encoded by a plasmid, there are two ways in GENE EDITING CAN UNINTENTIONALLY causing organisms, including, but not limited which foreign DNA can become inadvertently ADD FOREIGN DNA IN THE GENOME to, viruses.14 integrated into the genome of the plant being edited. First, the The study also found plasmid encoding The presence of unintended mutations has been restricted to CRISPR but has been found with that DNA from the Gene editing is a the gene-editing well documented in human and animal cells and other types of gene editing, too.13 genome of E. tool, either as a has begun to gain more attention in plants.11 potential mechanism for coli bacteria can whole, or fragments However, another unwanted outcome of gene Specifically, the researchers looked at the inadvertently horizontal gene transfer thereof, can become editing has received effects of CRISPR/ integrate into the integrated. Second, little attention and Cas gene editing of disease-causing orga Edited mouse genomes target organism’s DNA from the it is unclear to what in mouse cells genome. The source genome of the E. extent it occurs in unintentionally acquired and embryos and nisms, including, but not of the E. coli DNA coli bacteria used animal and plant found that edited was traced to the limited to, viruses to propagate the cells and what the bovine or goat DNA mouse genomes E. coli bacterial plasmid can often effects might be. unintentionally cells used to produce the vector plasmid. The contaminate the final plasmid preparation used acquired bovine or goat DNA. This was traced plasmid is a small circular DNA molecule that in the gene-editing process, and thus could end This outcome was highlighted in a study by to the use, in standard culture medium for carries the genes giving instructions for the up being integrated into the gene-edited plant’s Japanese researchers. The study found that mouse cells, of foetal calf serum and goat serum manufacture of the CRISPR/Cas components genome. even SDN-2 (gene alteration) applications extracted from cows or goats.12 (and in SDN-2 applications, the DNA of CRISPR/Cas gene editing, which aim not repair template) into the cells. Importantly, Foreign plasmid or bacterial genomic DNA to introduce foreign DNA, resulted in the Even more worrisome, amongst the DNA the researchers used standard methods of could be inadvertently incorporated during unintended incorporation of foreign and sequences inserted into the mouse genome vector plasmid preparation, so this type of plant gene editing. Therefore regulators must contaminating DNA into the genome of gene- were bovine and goat retrotransposons contamination could happen routinely.12 legally oblige developers to conduct appropriate edited organisms.12 This unwanted result is not (jumping genes) and mouse retrovirus DNA12 in-depth molecular genetic characterisation of These findings are clearly relevant to gene- their products to ascertain if such an outcome edited animals, but how do they relate to plant has taken place or not. gene editing? Tissue culture medium containing

26 27 SDN DISTINCTIONS NOT USEFUL GENE-EDITED CATTLE CONTAINED FOR JUDGING RISK ANTIBIOTIC RESISTANCE GENES

The distinction between SDN-1, -2, and -3 Indeed, all types of gene editing – SDN-1, -2, Claims of nature-identical or safe-by-design with Recombinetics, claimed that the gene is not useful for differentiating levels of risk and -3 – can be carried out at multiple locations gene-edited products should be viewed with editing used in the cattle was precise, that the for each type of gene-edited organism. This is of the genome using multiplex approaches, scepticism, as demonstrated by the case of the changes brought about are largely identical because SDN-1, -2, and -3 refer to the intention which target several genes at once, or in gene-edited hornless cattle. to what could have arisen naturally, and that of the gene editing and not the actual outcome, repeated, sequential applications.19,20,21 Thus any animals with unwanted traits would be whereas the outcome of a gene-editing event claims that the changes made are “small” and In 2019 researchers at the US Food and Drug excluded from breeding programmes.24 can be very different from the intention. “similar to what might happen in nature” are Administration (FDA) analysed the genomes of misleading, as several individually small changes two calves13 that had However, all these Also, even small changes in the genome can can combine to produce an organism that is been gene edited by These claims were claims were proven cause large effects.15,16 The London-based very different from the parent organism. While the biotech company false by what the FDA molecular geneticist Dr even small changes can Recombinetics using proven false by what scientists found. Michael Antoniou said, produce large effects, the TALEN tool the FDA scientists “The size of genetic The size of genetic a number of small in an SDN-3 (gene At one of the target changes does not changes made via gene insertion) procedure. found sites of the gene- determine risk, since changes does not editing can result in The aim of the genetic editing procedure small genetic changes determine risk, even greater changes, manipulation was to prevent the animals from within the calves’ genome, the POLLED gene may result in dramatic which increases growing horns by inserting into their genome had inserted as planned. However, at the other and novel effects. since small genetic the possibility of the POLLED gene, taken from conventionally intended gene editing site, two copies of the For example, a small changes may result in unintended alterations bred hornless cattle. entire circular plasmid DNA construction deletion or insertion in the edited plant’s that carried the following a gene- dramatic and novel biochemistry and Recombinetics scientists had claimed editing event could overall composition, that the gene editing used in the result in creating a new effects with unknown cattle was so precise that “our gene sequence, which consequences for animals are free of off-target can give rise to a novel mutant protein with both crop performance and the health of the events”.22 The company’s unknown functional consequences. This is why consumer. executives had told Bloomberg all of the mutations caused by gene editing must in 2017, “We know exactly be assessed on the basis of what they do, as well Thus the risks of both small and large changes where the gene should go, and as what type and how numerous they are.” must be carefully assessed. Although unwanted we put it in its exact location,” genetic changes have been studied in gene- and “We have all the scientific SDN-1 and -2 applications are often assumed to edited organisms to some extent, data that proves that there are be less disruptive than SDN-3 because there is no safety studies have been carried out no off-target no intention to permanently integrate foreign with gene-edited products. Such studies are effects.”23 DNA into the genome. However, there is no compulsory under EU laws before a GMO evidence that the mutations caused are fewer, product can be placed on the market. A commentary by academic smaller, or less risky in type. In fact, major researchers, some of mutations, including large deletions, insertions, whom were associated and rearrangements of DNA, have been found to be generated even by SDN-1 procedures.17,18

28 29 POLLED sequence, which acted as the repair expected, and we didn’t look for it”. He admitted The supposedly slow speed of conventional breeding – almost 10% of the cows in Germany in 2015 were template DNA in the SDN-3 procedure, that a more complete check “should have been programmes relative to gene editing was cited by bred to a polled bull.27 had been unintentionally integrated. These done”.23 both sets of authors.22,24 unintentionally integrated plasmids contained It seems that conventional breeding has already complete gene sequences that confer resistance As a result of the FDA scientists’ discovery, However, this does not seem to be true for Europe.27 achieved what GMO advocates claimed could only be to three antibiotics (neomycin, kanamycin, and Brazil cancelled its plans to create a herd of the According to a breeder of polled Holsteins in done quickly through gene-editing technology. The ampicillin).13 gene-edited hornless Pennsylvania, USA, Europeans “aggressively selected cost and time involved are not prohibitive; polled cattle.26 for the trait, and now they are years ahead of us as cattle are produced with high genetic merit; and It is not known if Developers cannot be far as polled genetics. Animal welfare legislation in good progress has been made in availability of polled the presence of these Developers cannot be Europe based on consumer pressure will drive even sires. antibiotic resistance trusted to self-regulate trusted to self-regulate further use of polled.”27 genes could affect and determine for and determine for This example shows that society needs to critically the health of the themselves whether Hendrik Albada, co-owner of the Hul-Stein Holstein evaluate claims that gene editing is the only or best animal or of people themselves whether the changes induced herd in the Netherlands, said polled sires are popular solution to a given problem. who consume its the changes induced by by gene editing are in Europe based on genetic merit alone products. However, safe or the same one risk that merits gene editing are safe as could happen investigation is that in nature. Strict these genes could regulation must transfer to disease-causing bacteria, which be in place to ensure thorough screening would then become resistant to antibiotics, for unintended effects. As commonly used threatening human and animal health.25 screening methods will miss many mutations, a combination of long-range PCR and long- The Recombinetics scientists had missed these read DNA sequencing must be used, as noted unintended effects because they used inadequate in chapter 2. In addition, safety studies must analytical methods.22 Tad Sontesgard, CEO of be conducted to better understand the risks to ORGANISMS WITH UNWANTED MUTATIONS Acceligen, a subsidiary of Recombinetics that public health and the environment posed by the owned the animals, said, “It was not something gene-edited organism. MAY NOT BE REMOVED FROM BREEDING PROGRAMMES

GMO developers often claim that gene-edited that GMO developers cannot be relied upon to organisms with genetic errors and unwanted identify genetic errors and unwanted traits13 traits will be and that strict eliminated Experience with first- regulation must from breeding be in place to WHY GENE EDITING programmes,24 generation GM crops enforce thorough or that the errors shows that backcrossing screening.28 RATHER THAN BREEDING? can be removed by subsequent as conducted by GMO Experience with backcrossing; thus first-generation The failure of the gene-edited hornless cattle venture this end, but in practice the cost would be prohibitive: developers does not reliably they are nothing GM crops shows raises an obvious question: Why didn’t the developers “No breeder can afford to undertake this approach.”24 to worry about. that backcrossing simply cross the gene into the elite Holstein breed In a separate paper, Recombinetics scientists cited a remove unwanted traits as conducted through breeding, instead of gene editing the Holstein? shortage of breeding sires producing commercially However, the case of the gene-edited cattle by GMO developers does not reliably remove available POLLED semen and the poor “genetic merit” that turned out to unexpectedly contain unwanted traits and that crops with such traits The team of academic scientists cited above, some of of polled Holstein sires – they said breeding for the antibiotic resistance genes (see above) shows have reached the market. whom were associated with Recombinetics, wrote POLLED trait brings along other undesirable traits that in principle, conventional breeding could achieve such as poor milk yield.22

30 31 For example, in the case of glyphosate-tolerant With GM vegetatively propagated crops, makes it possible to obtain the same effects techniques. Some scientists therefore argue that NK603 maize, an increase in certain compounds such as potatoes, bananas, and fruit trees, as the introduction of a foreign gene into the EU’s risk assessment guidelines should be was found in the GM crop compared with the the presence of large numbers of unwanted the organism (transgenesis) and those new expanded to take these risks into account.8,15,16 non-GM parent, which could prove either mutations is inevitable. This is because techniques make it possible to produce Interestingly, neither the Bayer scientist, nor protective or toxic, depending on context. In propagation takes place not by seeds produced genetically modified varieties at a rate out the European Court of Justice, nor the scientists addition, metabolic imbalances were found in by sexual reproduction (pollination), but by of all proportion to those resulting from who warn of the special risks of gene editing the GM maize, which could affect nutritional various asexual methods, including growing the application of conventional methods of support the notion that gene-edited organisms quality.29 These unwanted changes may from tubers (e.g. potatoes), cuttings (e.g. mutagenesis.”33 are safer than older-style transgenic GMOs. explain adverse health impacts observed from bananas), and grafting (e.g. fruit trees such as These claims are based on marketing concerns, consumption of the maize.30 In the case of GM apples) – generating a new plant from a part Gene-editing techniques pose new and different not science. MON810 Bt insecticidal maize, it contained of the parent plant. This means that mutations risks compared with older-style transgenic GM an allergen, zein, that was not present in the caused by genetic engineering processes parent crop.31 It is possible that the developer (including gene editing) cannot be bred out did not notice these changes, or if they did, by backcrossing and will persist into the final COMPARING GENE EDITING WITH deemed them unimportant. marketed product. MUTATION BREEDING IS MISLEADING GENE-EDITED ORGANISMS NOT SAFER Advocates of gene editing claim that it is lead to different risks. Just how risky mutation more precise and thus safer than mutation breeding is for health and environment remains THAN OLDER-STYLE GMOS breeding.34 But this claim is misleading because unknown because controlled studies have not it is the wrong comparison. Although mutation been done, though there is suggestive evidence It is a common misconception that gene-edited in the European Court of Justice ruling that breeding is used alongside conventional that it may be less risky than gene editing.8 organisms are safer than older-style GMOs. gene-edited organisms (called in the case “new breeding, it is a But there is no techniques/ minority method Just how risky mutation Nevertheless, scientific basis “The risks linked to the use methods of that cannot for the plant to this notion, mutagenesis”) be equated to breeding is for health and itself, mutation as confirmed by of those new techniques/ must be regulated conventional breeding is Bayer scientist Dr in the same way breeding. The environment remains widely recognized methods of mutagenesis as risky, Larry Gilbertson, as older-style standard method unknown because who said that might prove to be similar GMOs. of conventional unpredictable, the risks of new The court breeding is controlled studies have not and inefficient at producing techniques like to those which result explained: cross-breeding been done beneficial gene editing and and selection of from the production and mutations. older techniques “The risks linked desired traits. The Plant cells can be killed by exposure to the of genetic release of a GMO through to the use of those process can be made quicker and more efficient chemical or radiation, while many of the modification are new techniques/ by using the biotechnologies known as marker resulting plants are deformed, non-viable, and/ the same: “I don’t transgenesis’’ methods of assisted selection and genomic selection35,36 (use or infertile.37,38,39 think there’s a - European Court of Justice mutagenesis of these technologies does not in itself result fundamental might prove in a GMO). Standard conventional breeding Mutation breeding is recognised under EU law difference in the risk between these two to be similar to those which result from the has an undeniable history of safe use and is the as genetic modification. It is exempted from the technologies since they’re both fundamentally production and release of a GMO through technique that should be used as the comparator requirements of the regulations because (despite just changes in DNA.”32 transgenesis, to gene-edited crops. since the direct modification of the genetic the absence of research on risk) it is deemed to have a history of safe use.40 But this clearly does In 2018 this scientific reality was reflected material of an organism through mutagenesis As we have seen in chapter 3, gene editing is not apply to gene editing, which has no history different from mutation breeding and would of use, let alone safe use.8

32 33 17. Robinson C, Antoniou M. Science supports need to 30. Séralini G-E, Clair E, Mesnage R, et al. Republished subject gene-edited plants to strict safety assessments. study: long-term toxicity of a Roundup herbicide REGULATORY OVERSIGHT CRUCIAL GMWatch.org. Published November 20, 2019. https:// and a Roundup-tolerant genetically modified maize. www.gmwatch.org/en/news/latest-news/19223 Environmental Sciences Europe. 2014;26(14). doi:10.1186/ Gene editing technology produces unintended • always have the ability to remove them (with s12302-014-0014-5 18. Biswas S, Tian J, Li R, et al. Investigation of outcomes, which can pose risks to human vegetatively propagated crops). CRISPR/Cas9-induced SD1 rice mutants highlights 31. Zolla L, Rinalducci S, Antonioli P, Righetti PG. and animal health and the environment. Even the importance of molecular characterization in Proteomics as a complementary tool for identifying plant molecular breeding. Journal of Genetics and unintended side effects occurring in transgenic maize if developers are optimistic that unwanted For these reasons, stringent regulatory Genomics. Published online May 21, 2020. doi:10.1016/j. seeds as a result of genetic modifications. J Proteome Res. outcomes can be eliminated, they do not: oversight is crucial, as FDA scientist Steven M. jgg.2020.04.004 2008;7:1850-1861. doi:10.1021/pr0705082 • properly screen for them – arguably because Solomon recommended for gene-edited animals 19. Wang H, La Russa M, Qi LS. CRISPR/Cas9 32. Fortuna G, Foote N. Bayer scientist: “Regulation and that would defeat the purpose of using gene in the US,28 and as the European Court of in genome editing and beyond. Annual Review risk assessment must evolve with technology.” EurActiv. of Biochemistry. 2016;85(1):227-264. doi:10.1146/ com. Published online December 11, 2019. Accessed editing to gain time Justice has ruled with regard to all gene-edited annurev-biochem-060815-014607 January 8, 2021. https://www.euractiv.com/section/ • reliably remove them organisms in the EU.33 agriculture-food/video/bayer-scientist-regulation-and- 20. Zetsche B, Heidenreich M, Mohanraju P, et al. risk-assessment-must-evolve-with-technology/ Multiplex gene editing by CRISPR–Cpf1 using a single crRNA array. Nature Biotechnology. 2017;35(1):31-34. 33. European Court of Justice. C-528/16 - Confédération doi:10.1038/nbt.3737 Paysanne and Others: Judgement of the Court. (European Court of Justice 2018). Accessed September 21. Raitskin O, Patron NJ. Multi-gene engineering 27, 2019. http://curia.europa.eu/juris/documents. REFERENCES in plants with RNA-guided Cas9 nuclease. Curr jsf?num=C-528/16 Opin Biotechnol. 2016;37:69-75. doi:10.1016/j. 1. Bayer. Here are the facts about agriculture and 10. European Network of Scientists for Social and copbio.2015.11.008 34. Askew K. CRISPR genome editing to address food nutrition. Published online November 2018. https:// Environmental Responsibility (ENSSER). ENSSER security and climate change: “Now more than ever we release.ace.bayer.com/sites/default/files/2020-04/here- Statement: New Genetic Modification Techniques and 22. Carlson DF, Lancto CA, Zang B, et al. Production are looking to science for solutions.” foodnavigator.com. are-the-facts-about-agriculture-and-nutrition-brochure. Their Products Pose Risks That Need to Be Assessed. of hornless dairy cattle from genome-edited cell lines. Published online May 4, 2020. Accessed January 29, 2021. pdf European Network of Scientists for Social and Nature Biotechnology. 2016;34:479-481. doi:10.1038/ https://www.foodnavigator.com/Article/2020/05/04/ Environmental Responsibility (ENSSER); 2019. https:// nbt.3560 CRISPR-genome-editing-to-address-food-security-and- 2. Corteva Agriscience. Frequently Asked Questions. ensser.org/publications/2019-publications/ensser- climate-change-Now-more-than-ever-we-are-looking- crispr.corteva.com. Published 2021. Accessed statement-new-genetic-modification-techniques-and- 23. Regalado A. Gene-edited cattle have a major screwup to-science-for-solutions January 11, 2021. https://crispr.corteva.com/ their-products-pose-risks-that-need-to-be-assessed/ in their DNA. MIT Technology Review. Published online faqs-crispr-cas-corteva-agriscience/ August 29, 2019. Accessed March 20, 2020. https://www. 35. Cobb JN, Biswas PS, Platten JD. Back to the future: 11. GMWatch. Gene editing: Unexpected outcomes technologyreview.com/s/614235/recombinetics-gene- revisiting MAS as a tool for modern plant breeding. 3. EuropaBio. Achieving the potential of genome editing. and risks. GMWatch.org. Published August 3, 2020. edited-hornless-cattle-major-dna-screwup/ Theor Appl Genet. 2019;132(3):647-667. doi:10.1007/ EuropaBio.org. Published June 2019. Accessed January Accessed January 11, 2021. https://www.gmwatch.org/ s00122-018-3266-4 10, 2021. https://www.europabio.org/cross-sector/ en/67-uncategorised/19499-gene-editing-unexpected- 24. Carroll D, Van Eenennaam AL, Taylor JF, Seger publications/achieving-potential-genome-editing outcomes-and-risks J, Voytas DF. Regulate genome-edited products, not 36. Arruda MP, Lipka AE, Brown PJ, et al. Comparing genome editing itself. Nat Biotechnol. 2016;34(5):477-479. genomic selection and marker-assisted selection for 4. Corteva Agriscience. CRISPR Q&A – For internal 12. Ono R, Yasuhiko Y, Aisaki K, Kitajima S, Kanno doi:10.1038/nbt.3566 Fusarium head blight resistance in wheat (Triticum use only. Published online May 28, 2019. https:// J, Hirabayashi Y. Exosome-mediated horizontal aestivum L.). Mol Breeding. 2016;36(7):84. doi:10.1007/ crispr.corteva.com/wp-content/uploads/2019/05/ gene transfer occurs in double-strand break repair 25. Nawaz MA, Mesnage R, Tsatsakis AM, et al. s11032-016-0508-5 FINAL_For-Internal-Use-Only_Corteva-CRISPR-QA- during genome editing. Commun Biol. 2019;2(1):1-8. Addressing concerns over the fate of DNA derived from UPDATED-5.28.19.pdf doi:10.1038/s42003-019-0300-2 genetically modified food in the human body: A review. 37. Acquaah G. Principles of Plant Genetics and Breeding. Food Chem Toxicol. 2018;124:423-430. doi:10.1016/j. Wiley-Blackwell; 2007. http://bit.ly/17GGkBG 5. Tuladhar R, Yeu Y, Piazza JT, et al. CRISPR-Cas9- 13. Norris AL, Lee SS, Greenlees KJ, Tadesse DA, fct.2018.12.030 based mutagenesis frequently provokes on-target Miller MF, Lombardi HA. Template plasmid integration 38. Van Harten AM. Mutation Breeding: Theory and mRNA misregulation. Nat Commun. 2019;10(1):1-10. in germline genome-edited cattle. Nat Biotechnol. 26. Molteni M. Brazil’s plans for gene-edited cows got Practical Applications. Cambridge University Press; 1998. doi:10.1038/s41467-019-12028-5 2020;38(2):163-164. doi:10.1038/s41587-019-0394-6 scrapped—Here’s why. Wired. Published online August 26, 2019. Accessed June 7, 2020. https://www.wired. 39. GM Science Review Panel. First Report: An 6. Mou H, Smith JL, Peng L, et al. CRISPR/Cas9- 14. Latham J. Gene-editing unintentionally adds com/story/brazils-plans-for-gene-edited-cows-got- Open Review of the Science Relevant to GM Crops mediated genome editing induces exon skipping by bovine DNA, goat DNA, and bacterial DNA, mouse scrappedheres-why/ and Food Based on Interests and Concerns of the alternative splicing or exon deletion. Genome Biology. researchers find. Independent Science News. https:// Public. DEFRA; 2003. https://www.researchgate.net/ 2017;18:108. doi:10.1186/s13059-017-1237-8 www.independentsciencenews.org/health/gene- 27. O’Keefe K. Polled Holsteins: Past, present and publication/272998451_GM_SCIENCE_REVIEW_ editing-unintentionally-adds-bovine-dna-goat-dna- future. Progressive Dairy. Published online October FIRST_REPORT_An_open_review_of_the_science_ 7. Smits AH, Ziebell F, Joberty G, et al. Biological and-bacterial-dna-mouse-researchers-find/. Published 18, 2016. Accessed January 10, 2021. https:// relevant_to_GM_crops_and_food_based_on_interests_ plasticity rescues target activity in CRISPR knock September 23, 2019. www.progressivedairy.com/topics/a-i-breeding/ and_concerns_of_the_public outs. Nat Methods. 2019;16(11):1087-1093. doi:10.1038/ polled-holsteins-past-present-and-future s41592-019-0614-5 15. Eckerstorfer M, Miklau M, Gaugitsch. New Plant 40. European Parliament and Council. Directive Breeding Techniques and Risks Associated with Their 28. Solomon SM. Genome editing in animals: why FDA 2001/18/EC of the European Parliament and of the 8. Kawall K, Cotter J, Then C. Broadening the GMO risk Application. Environment Agency Austria; 2014. http:// regulation matters. Nat Biotechnol. 2020;38(2):142-143. Council of 12 March 2001 on the deliberate release into assessment in the EU for genome editing technologies www.ekah.admin.ch/fileadmin/ekah-dateien/New_ doi:10.1038/s41587-020-0413-7 the environment of genetically modified organisms in agriculture. Environmental Sciences Europe. Plant_Breeding_Techniques_UBA_Vienna_2014_2.pdf and repealing Council Directive 90/220/EEC. Official 2020;32(1):106. doi:10.1186/s12302-020-00361-2 29. Mesnage R, Agapito-Tenfen SZ, Vilperte V, et al. An Journal L. 2001;106:1-39. http://eur-lex.europa.eu/ 16. Eckerstorfer MF, Dolezel M, Heissenberger A, et integrated multi-omics analysis of the NK603 Roundup- legal-content/en/TXT/?uri=CELEX%3A32001L0018 9. Agapito-Tenfen SZ, Okoli AS, Bernstein MJ, Wikmark al. An EU perspective on biosafety considerations for tolerant GM maize reveals metabolism disturbances O-G, Myhr AI. Revisiting risk governance of GM plants developed by genome editing and other new caused by the transformation process. Scientific Reports. plants: The need to consider new and emerging gene- genetic modification techniques (nGMs). Front Bioeng 2016;6:37855. doi:10.1038/srep37855 editing techniques. Front Plant Sci. 2018;9. doi:10.3389/ Biotechnol. 2019;7. doi:10.3389/fbioe.2019.00031 fpls.2018.01874

34 35 In fact, patents generally encompass specific researchers confirmed that a single base pair genomic sequences independently of how they change can be detected with standard GMO 5. Gene-edited products are derived. For example, crops developed detection technology based on polymerase chain through mutation breeding can be identified reaction (PCR) methodology. Thus it is likely on the basis of the that detection methods are detectable specific sequences that When the specific can be developed for characterise them and most, if not all, gene- that are described in the sequences that edited organisms, patent. characterise a crop according to the researchers, provided When these specific are known, not enough information on sequences are known, the nature of the edit is not only the developer only the developer available.4 MYTH but also others can but also others can REALITY develop specific They stated: “Our work Gene-edited products detection methods for develop specific demonstrates that it may Methods can be cannot be distinguished these crops. This has detection methods be possible to develop developed to detect all been done for Cibus’ event-specific, GMO from products developed SU Canola. Cibus has regulation compliant products of gene editing, developed its own detection method to identify detection methods for virtually any gene-edited through conventional its product, and submitted it to Canadian organism based on information disclosed by provided information 3 breeding. authorities, but the authorities refused to make the developer or gathered from the public on the genetic change it available to Canadian NGOs on grounds domain.”4 that it was confidential business information. is available. However, a team of scientists has developed an open-source detection method for this GM crop based on publicly available information.4 Industry associations have claimed that many detection gene-edited products cannot be distinguished and SU Canola represented a particularly from products developed with conventional identification challenging case, since the alteration in breeding.1 And according to Bayer, a change of a wide range of its genetic blueprint consists of only made through gene editing is “indistinguishable genetic modifications, a “single base pair” (DNA base unit) from a conventional breeding breakthrough or from the smallest – e.g. change within a specific gene. The a natural mutation”.2 a point mutation of The objective of these Any patented seed a single nucleotide claims seems to be product can be (DNA base unit) – to the to persuade the EU largest, e.g. insertion of authorities not to even distinguished from large genetic sequences, try to apply the EU’s provided information GMO regulations to other products on the genetic change gene editing. is available. Also, any patented seed product can be distinguished However, already-available, standard GMO from other products. Otherwise it would be detection techniques allow unambiguous impossible to enforce patent rights.

36 37 Unknown gene-edited crops are just another demands fundamental changes in the regulatory category of GM products that GMO screening regime for GMOs. UNKNOWN GENE-EDITED CROPS methods can miss and that must be detected by event-specific methods such as the one The researchers who developed the test for SU Critics of the open-source SU Canola test have circulation. Seed companies talk about gene developed for SU Canola. The presence of gene- Canola believe it may be possible in the future focused on the fact that it does not detect the editing when they use it because they want to edited products in the commercial food system to develop screening methods for various GM method used. Some – like the European be able to profit in the marketplace from the use does not create a new set of circumstances that classes of gene-edited crops.4 Plant Science Organisation (EPSO) – also said of these new GM techniques. that it does not solve the problem of unknown genetic modifications.5 So far, only two gene-edited crops have been commercialised : Cibus’s SU Canola and TRANSPARENCY REQUIRED However, EU law does not require that Calyxt’s “high oleic” asoybean with an altered detection tests are able to specify the GM oil profile. Thus far it has proved possible to In the meantime, transparency must be Once information has been disclosed by the method used to develop track a significant number demanded from developers of gene-edited developer, it should be organised in a publicly the crop. A scientific The detection of of gene-edited products organisms. Under the EU’s GMO regulations, accessible resource. We can use what is already review by researchers developed worldwide for agricultural biotech companies are required there – the Biosafety Clearing-House of the from Germany’s Federal commercial markets, as to provide a detection Cartagena Protocol unknown GMOs 10 Office of Consumer the Julius Kühn Institute method and “reference” It cannot be the job on Biosafety, the Protection and Food Safety has never been in Germany has done sample material for each EUginius GMO database (BVL) and Julius Kühn solely reliant on for a peer-reviewed GMO that is authorised, of governments, civil of the Federal Office of Institute recognised that publication.8 though the sector has Consumer Protection GMO detection methods the detection not yet submitted any society, or academia and Food Safety (BVL) generally do not allow any methods used in Also, the potential for gene-edited GMOs to be to fill knowledge in Germany and conclusions on the process unknown GMOs to slip marketed in the EU. Wageningen Food used, whether they be through official controls is gaps created by Safety Research in The the laboratory 11 gene-editing techniques not new. The same is true Meanwhile researchers industry secrecy Netherlands, and the or older-style transgenic genetic modification for the GM crops that have been successfully at North Carolina State register set up by the techniques. However, the researchers regulated in Europe and other countries for the University are calling European Commission 12 commented that “bioinformatics and statistical last two and a half decades. for a coalition of biotech industry, government for EU-authorised and withdrawn GMOs. considerations might help to evaluate whether a and non-government organizations, trade The EU must ensure that countries wishing to detected sequence was potentially introduced by Today’s strategies for screening for unknown organizations, and academic experts to work export to the bloc participate in these registers. genome modification”.6 GMOs do not capture all of them. They only together to provide basic information about identify those that carry certain common gene-edited crops to lift the veil on how plants The European Commission’s register of EU- The detection of unknown GMOs has never genetic sequences that are used as “screening are modified and provide greater transparency authorised GMOs is required by EU law to also been solely reliant on the detection methods targets”. But the number of GM crops lacking on the presence and use of gene editing in food “contain, where available, relevant information used in the laboratory. The EU’s Joint Research common sequences has been increasing in supplies. They believe that such transparency is concerning GMO which are not authorised 13 Centre said in 2017 that the most efficient way recent years. It is possible that currently there crucial to building public trust and confidence in the European Union”. The Commission 9 to test imports for unknown GMOs was to are unauthorised GMOs in the marketplace in gene-edited products. and/or member states should work with check authorisations in other countries, patent that have not been detected because they do not international partners to meet this requirement. applications, scientific publications, and other carry any common sequences. No one claims However, the primary responsibility for information to apply a targeted approach. The that for this reason, the EU GMO legislation transparency over gene-edited products lies laboratory detection test can then be used to is impossible to enforce and thus useless. with their developers. It cannot be the job provide confirmation of information gathered By analogy, no one would suggest legalising of governments, civil society, or academia through other means.7 burglary because criminal laws do not prevent to fill knowledge gaps created by industry In addition, it is unlikely that a large number all burglaries. secrecy. of unknown gene-edited crops will be in

38 39 REFERENCES 6. Gene-editing

1. European Seed. 22 European business organisations 8. Menz J, Modrzejewski D, Hartung F, Wilhelm R, ask the EU for pro-innovation rules for plant breeding. Sprink T. Genome edited crops touch the market: A view technology is owned European-Seed.com. Published April 24, 2019. on the global development and regulatory environment. Accessed January 12, 2021. https://european-seed. Front Plant Sci. 2020;11. doi:10.3389/fpls.2020.586027 com/2019/04/22-european-business-organisations-ask- the-eu-for-pro-innovation-rules-for-plant-breeding/ 9. Kuzma J, Grieger K. Community-led governance for gene-edited crops. Science. 2020;370(6519):916-918. and controlled by big 2. Bayer. Here are the facts about agriculture and doi:10.1126/science.abd1512 nutrition. Published online November 2018. https:// release.ace.bayer.com/sites/default/files/2020-04/here- 10. Conventional on Biological Diversity. Biosafety are-the-facts-about-agriculture-and-nutrition-brochure. Clearing-House. The Biosafety Clearing-House (BCH). Published 2021. Accessed January 29, 2021. https://bch. corporations pdf cbd.int/ 3. Government of Canada. DD 2013-100: Determination of the safety of Cibus Canada Inc.’s canola (Brassica napus 11. EUginius. EUginius: The European GMO database. L.) event 5715. www.inspection.gc.ca. Published April 16, Published 2021. Accessed January 29, 2021. https:// 2015. Accessed January 3, 2021. https://www.inspection. euginius.eu/euginius/pages/home.jsf gc.ca/plant-varieties/plants-with-novel-traits/approved- under-review/decision-documents/dd-2013-100/ 12. European Commission. Genetically modified eng/1427383332253/1427383674669 organisms: Community register of GM food and feed. webgate.ec.europa.eu. Published 2017. https://webgate. MYTH 4. Chhalliyil P, Ilves H, Kazakov SA, Howard SJ, ec.europa.eu/dyna/gm_register/index_en.cfm Johnston BH, Fagan J. A real-time quantitative PCR method specific for detection and quantification of 13. European Parliament and Council. Regulation (EC) Gene editing, and the REALITY the first commercialized genome-edited plant. Foods. No. 1830/2003 of the European Parlliament and of the 2020;9(9):1245. doi:10.3390/foods9091245 Council of 22 September 2003 concerning the traceability and labelling of genetically modified organisms and the CRISPR tool in particular, 5. EPSO. EPSO statement “Detecting a point mutation traceability of food and feed products produced from Gene editing technology does not clarify its origin.” EPSO. Published September genetically modified organisms and amending Directive puts the power of genetic 9, 2020. Accessed January 12, 2021. https://epsoweb.org/ 2001/18/EC. Official Journal of the European Union. for agricultural use is epso/epso-statement-detecting-a-point-mutation-does- Published online October 18, 2003:L 268/24-L 268/28. engineering into the not-clarify-its-origin/2020/09/09/ http://eur-lex.europa.eu/LexUriServ/LexUriServ. do?uri=OJ:L:2003:268:0024:0028:EN:PDF already firmly under 6. Grohmann L, Keilwagen J, Duensing N, et al. hands of hundreds of Detection and identification of genome editing in plants: the control of the Challenges and opportunities. Front Plant Sci. 2019;10. thousands of scientists, doi:10.3389/fpls.2019.00236 multinationals that 7. European Network Working Group of GMO including those Laboratories. Detection, Interpretation and Reporting on dominate the seed and the Presence of Authorised and Unauthorised Genetically working in publicly Modified Materials.; 2017. https://gmo-crl.jrc.ec.europa. agrochemicals markets. eu/ENGL/docs/WG-DIR-Final-Report.pdf funded institutes and small companies. Corteva has become the main gatekeeper of CRISPR patents in the agricultural arena. Advocates claim that gene-editing techniques, especially those using the CRISPR/Cas system, whether can democratise genetic engineering because due to expense they are cheaper and easier to apply than older or just technical genetic modification techniques. Jennifer difficulty”.1 Bayer calls CRISPR Doudna, one of CRISPR’s inventors, said the the “most ‘democratic’” gene-editing tool, which technology “became a democratising tool that is so “cheap and simple” that it can be used by allowed labs to do experiments that in the “universities and institutes that do not have past had been prohibitive for various reasons, major research budgets”.2

40 41 It is further argued that if gene editing were universities, non-profit organisations, exempted from the EU’s burdensome and and small and medium-sized enterprises LICENSING AGREEMENTS expensive-to-comply-with GMO regulations, (SMEs).3,4 The seed industry claims Once technology patents are granted, patent company Caribou Biosciences), with licensees it would be removed from the control of the that GMO regulations “prevent most of owners can conclude licensing agreements with DowDuPont (now Corteva) and Bayer/ big agbiotech multinationals and be made Europe’s plant breeding companies from companies allowing them to use the technology Monsanto, are particularly important.6,8 available to public research institutes and developing and using these methods”.5 in certain areas or in a specific application. DowDuPont concluded licensing These agreements can be exclusive or non- agreements not only with one of exclusive. Other companies can obtain licensing the holders of the foundational TECHNOLOGY PATENTS agreements only if the rights to use the patents CRISPR technology patents (the are granted non-exclusively to a licensee. Broad Institute), but also with Claims of democratisation through new GM building on the protected invention, as research An overview of CRISPR-based gene-editing all relevant institutions, techniques must be viewed in the light of the exceptions to patent rights are usually very technology licensing agreements was published including the companies fact that these strictly formulated. in Science in 2017.8 Caribou Biosciences and techniques are Patent holders have the ERS Genomics, and the patented, as are The Broad Institute In the areas of CRISPR gene-edited plants University of Vilnius.3,6 their products right for up to 20 years of MIT and Harvard, and livestock, licensing agreements reached – the plants the University of by patent owners, the Broad Institute and and animals to prohibit others from California, the the University of California (or its spinoff developed using University of Vilnius them. Patents are exploiting the patented in Lithuania, and monopoly rights. invention or to charge the University of Patent holders Vienna are the CARIBOU BIOSCIENCES have the right for royalties for its use main institutional up to 20 years to “inventors” of CRISPR AND ERS GENOMICS prohibit others from exploiting the patented technology.6,7,8,9 Between them they have invention or to charge royalties for its use. filed (and fought each other over9) hundreds Corteva (the agricultural division spun off by another CRISPR technology inventor This is not just about limiting commercial of foundational patents, some of which have from DowDuPont) is the main gatekeeper for and patent owner, Emmanuelle Charpentier, 10 exploitation, but also further innovation. already been granted in Europe.6 CRISPR patents in the agricultural arena and as a “licensing engine” that “exists to make the Exclusive patent rights prohibit others from has gained unprecedented market power due to [CRISPR] technology more broadly available its ability to grant access to this patent pool.6 To under appropriate commercial licences”. understand why, ERS Genomics we need to learn has signed non- the history of the The story begins with exclusive and CRISPR licensing two biotech startups co- exclusive licensing agreements. agreements founded by the inventors with companies The story begins of CRISPR technology operating in with two biotech different fields.8 startups co-founded by the inventors of CRISPR technology. DuPont (later DowDuPont and now Corteva) The first, Caribou Biosciences, was co-founded concluded its licensing agreement with in 2011 by one of the inventors of CRISPR- Caribou Biosciences in 2015. In the deal, based gene-editing technology, Jennifer DuPont received exclusive rights for CRISPR Doudna from the University of California. The technology applications in major row crops second, ERS Genomics, was co-founded in 2013 and non-exclusive rights in other agricultural

42 43 applications.11 In 2016 Caribou reached a deal use CRISPR technology in the agricultural Both Bayer/Monsanto and DowDuPont have international patent applications, while Bayer/ with the company Genus in which the latter area. ERS Genomics also granted sub-licensing applied for patents on glyphosate-tolerant Monsanto follows in second place with more received an exclusive licence to use CRISPR rights to DuPont. DuPont’s agricultural division plants produced with the CRISPR-mediated than 30. Calyxt… comes in at more than 20. technology in certain livestock species.12 was spun off in 2019 as an independent entity gene-editing process. This means that the core Syngenta and BASF are also involved, and a few named Corteva. Thus Corteva achieved its agricultural GMO patents have also DuPont also reached an exclusive licensing dominance of the CRISPR technology in the business – the been applied for by agreement in 2018 with ERS Genomics. The agricultural field. marketing of Both Bayer/Monsanto and traditional breeding agreement gave DuPont exclusive rights to herbicide-tolerant DowDuPont have applied companies such as plants such as soy, Rijk Zwaan and corn, oilseed rape/ for patents on glyphosate- KWS.”6 canola and cotton DEMOCRATISATION OR PATENT CARTEL ? – can continue tolerant plants produced A 2016 review of to be protected with the CRISPR- the intellectual Jean Donnenwirth of DowDuPont (now conditions include appropriate fees, reporting by new patent property rights Corteva) presented the company’s agreements obligations, compliance with guidelines, and applications in the mediated gene-editing landscape by Egelie 6 on 5 November 2018 at a meeting between the confidentiality. The first company to licence future.6 process and colleagues EU Commission and various interest groups, CRISPR technology under these conditions in found that “larger according to Dr Christoph Then of Testbiotech, 2018 was the US company Simplot, The owners of industry players, who was present. According to Donnenwirth, which develops GM potatoes.13 In 2019, a the patents are largely the same multinationals with Dow and DuPont at the forefront, already DowDuPont succeeded in combining 48 basic French company, Vilmorin & Cie, followed.14 that dominate the GMOs and agrochemicals appear to be more in control of the technology’s patents into a common patent pool (35 patents markets. Christoph Then wrote in 2019 : agricultural and food applications.”15 from the Broad Institute, 4 from the University Christoph Then commented, “DowDuPont “DowDuPont leads the field in the new genetic of California, 2 from the University of Vilnius, has unprecedented market power thanks to engineering methods for crops, with around 60 and 7 from DowDuPont).6 the possibility of granting access to this patent pool: What is on the one hand touted as a Donnenwirth said that access to this number ‘democratisation’ of patent law turns out, on of patents is necessary for full use of the closer examination, to be a means of controlling LOST ACCESS TO technology in plant breeding. DowDuPont competitors and protecting a dominant TRADITIONAL CULTIVARS can offer bundled, non-exclusive licenses position. DowDuPont becomes, so to speak, the giving access to this patent pool. The gatekeeper of an international patent cartel.”6 In a discussion dominated by concerns about with expanded markets in new biotech crops, or gaining access to CRISPR technology, it is mined as genetic resources for breeding gene- easy, as pointed out by Maywa Montenegro de edited varieties”.1 There is a danger that farmers Wit of the University of California, to forget will be forced to pay for access to gene-edited PATENTS ON “NEW GM” CROPS the crucial issue of farmers “losing access to seeds and breeds, but lose access to non-GM DOMINATED BY DOWDUPONT, traditional cultivars that might be displaced seeds and breeds in the process. BAYER/MONSANTO ACCESS TO THE TECHNOLOGY FOR SMES The ‘democratic’ credentials of gene editing According to Christoph Then, patent are determined not only by access to the applications involving new and old genetic ACTING ALONE IS ILLUSORY technologies but also by access to their products engineering relate to plants with modified Could the de-regulation of gene editing help This prospect is highly unlikely, according to – gene-edited crops and seeds. But just like the growth and yield, composition, or resistance to empower small and medium size enterprises molecular geneticist Dr Michael Antoniou, technologies, the products are circumscribed by disease, as well as technical modifications of the (SMEs) to develop the gene-edited crops and who has many years’ experience of developing intellectual property rights. nucleases. As a rule, the patents cover methods, foods that will enable us to meet the challenges patented biotech products for medical research seeds, plants and often also the harvest.6 of climate change?4,16 with SMEs and larger companies.4

44 45 He explained that different types of licences CRISPR technology “in the hands of many”, exist for technologies like CRISPR gene editing, resulting in “a wide array of benefits for the GAME FOR BIG PLAYERS which industry-based researchers (including global food supply”.3 But scientists will only be those working in SMEs) must take out at able to use CRISPR for basic non-commercial Due to the expense involved, SMEs on their This business model is not considered a different stages of product development. These research, not for developing commercial own will never be able to afford the patents cause for lamentation. On the contrary, include evaluation, research, and commercial products. Maywa Montenegro de Wit and commercial licensing agreements that it is celebrated as a path to success for all licences. Evaluation licenses are granted to concluded: “Despite the opening up of CRISPR govern gene editing. involved, including researchers by the patent owners or their IP [intellectual property] for non-commercial So the system in At the end of the day, the individuals and sub-licensing affiliate companies to allow the research, CRISPR’s commercial development the agricultural SME that invented the researchers to do preliminary work to see if remains tightly bound up in patents and biotech market is, gene editing is a game product.4 the technology could licensing agreements and will remain, that be useful. If the – a landscape already researchers based in for big players and However, at the end of researchers want to “Despite the opening up showing strong small companies or will remain so the day, gene editing is pursue a particular signs of agroindustry universities, often with a game for big players application, they can of CRISPR IP for non- dominance.”1 industry funding, “invent” a GMO and partner and will remain so. The notion that CRISPR apply to the patent commercial research, with investors and/or a large company to will grant small players access to the technology owners for research Plant breeders patent the product, obtain regulatory approval, is a myth. licenses.4 CRISPR’s commercial using conventional and bring it to market. The inventors and their development remains breeding to develop institutions enjoy a profit-sharing arrangement Evaluation and a new plant variety with the investors or large partner company. research licences are tightly bound up in can protect it through Often in this process, the SME is bought up by often granted quite plant breeders’ rights. larger companies.4 cheaply, and fees patents and licensing But if they decide to can even be waived agreements’’ use CRISPR (whether altogether, since the or not the technology technology owners - Maywa Montenegro is regulated as GM), PATENTS THE DRIVING FORCE OF OLD want it to be used to de Wit they will need to develop a product learn to navigate a AND NEW GENETIC ENGINEERING that can be far more complex commercialised. and expensive process. They will have to Experience with genetic engineering to date many plant breeding companies.17 Even when evaluation and research licence compensate the CRISPR patent holder(s) both shows that patent law has been the driving With new genetic engineering techniques, fees are charged, a typical SME could afford at the research and development stage and also force behind development. The advent of this strategy has continued and been expanded. them.4 But at the commercialisation stage, at the commercialisation stage. genetic engineering Already, corporations things can quickly get very expensive, with Patent and licensing fees will raise the cost of marked the first time such as Corteva and technology patent holders demanding high The advent of variety development considerably. that patent law was Bayer/Monsanto control payments for use of the technology, in the form systematically applied genetic engineering large parts of the of commercial licence fees and royalty payments Patenting fees can easily accumulate to six- to plant breeding. Large seed market.17 Patented on product sales. marked the first figure sums, since patents must be applied for agrochemical companies, genetic engineering – and patent lawyers engaged – in each territory which had previously time that patent law techniques such as As an example, Corteva has made a where intellectual property rights are sought. protected their pesticides CRISPR gene-editing commitment to allow free access to the CRISPR The patenting process can drag on for years, with patents, now also was systematically technology help them technology for “universities and nonprofit 4 with lawyers’ fees rising all the while. applied for patents on extend and deepen this organizations for academic research”. The applied to plant GM seeds and at the control.6 company has claimed that this will put the same time bought up breeding

46 47 Therefore gene-editing technology will will further consolidate power within the big not make genetic engineering accessible to multinationals. publicly funded breeding programmes, but

REFERENCES 7. Gene editing is not

1. Montenegro de Wit M. Democratizing CRISPR? 10. O’Malley M. CRISPR’s licensing landscape decoded. a fast or reliable route Stories, practices, and politics of science and Intellectual Property Magazine. Published online January governance on the agricultural gene editing frontier. 2, 2018. Kapuscinski AR, Fitting E, eds. Elementa: Science of the Anthropocene. 2020;8(9). doi:10.1525/elementa.405 11. DuPont. DuPont and Caribou Biosciences announce strategic alliance. BioSpace.com. Published October 8, to desired outcomes 2. Bayer. Here are the facts about agriculture and 2015. Accessed December 7, 2020. https://www.biospace. nutrition. Published online November 2018. https:// com/article/dupont-and-caribou-biosciences-announce- release.ace.bayer.com/sites/default/files/2020-04/here- strategic-alliance-/ are-the-facts-about-agriculture-and-nutrition-brochure. pdf 12. Caribou Biosciences. Genus and Caribou Biosciences announce exclusive collaboration for leading CRISPR- 3. Cameron D. DuPont Pioneer and Broad Institute Cas9 gene editing technology in livestock species. join forces to enable democratic CRISPR licensing in cariboubio.com. Published May 18, 2016. Accessed agriculture. Broad Institute. Published October 18, 2017. December 7, 2020. https://cariboubio.com/in-the-news/ Accessed December 4, 2020. https://www.broadinstitute. press-releases/genus-and-caribou-biosciences-announce- org/news/dupont-pioneer-and-broad-institute-join- exclusive-collaboration-leading forces-enable-democratic-crispr-licensing-agriculture 13. Nosowitz D. Potato company Simplot licenses 4. Robinson C. Why regulation of gene editing will DowDuPont’s gene editing tech. Modern Farmer. MYTH REALITY not hurt small and medium size companies. GMWatch. Published August 7, 2018. Accessed December 7, 2020. https://gmwatch.org/en/news/latest-news/19239. https://modernfarmer.com/2018/08/potato-company- Published November 28, 2019. simplot-licenses-dowduponts-gene-editing-tech/ Gene editing achieves There are many lengthy 5. Euroseeds. Position: Plant Breeding Innovation. 14. Michalopoulos S. Corteva signs first major gene desired traits more steps in bringing a Euroseeds; 2018. https://www.euroseeds.eu/app/ editing deal with European company. EurActiv.com. uploads/2019/07/18.1010-Euroseeds-PBI-Position-1.pdf Published online December 10, 2019. Accessed January 12, 2021. https://www.euractiv.com/section/agriculture- quickly than gene-edited product to 6. Then C. Neue Gentechnikverfahren und food/news/corteva-signs-first-major-gene-editing-deal- Pflanzenzucht: Patente-Kartell für große Konzerne. with-european-company/ conventional breeding. market, even without Forum Umwelt & Entwicklung. Published online February 2019:10-11. https://tinyurl.com/y5hcu996 15. Egelie KJ, Graff GD, Strand SP, Johansen B. The emerging patent landscape of CRISPR–Cas gene editing considering regulation, 7. University of California Office of the President. technology. Nature Biotechnology. 2016;34(10):1025- University of California’s foundational CRISPR- 1031. doi:10.1038/nbt.3692 and conventional breeding Cas9 patent portfolio reaches 20 total U.S. patents. prnewswire.com. Published December 31, 2019. Accessed 16. Foote N. MEPs slam gene-editing court ruling as December 7, 2020. https://www.prnewswire.com/ damaging for SMEs. www.euractiv.com. https://www. Gene editing is promoted as the fastest and most is more successful in news-releases/university-of-californias-foundational- euractiv.com/section/agriculture-food/news/meps- 1,2 crispr-cas9-patent-portfolio-reaches-20-total-us- slam-gene-editing-court-ruling-as-damaging-for-smes/. efficient way to achieve plant breeding goals. achieving desired traits. patents-300980003.html Published November 22, 2019. Accessed December 9, According to Corteva, “CRISPR-produced plants 2019. 8. Contreras JL, Sherkow JS. CRISPR, surrogate can be developed in just a few years versus what often licensing, and scientific discovery. Science. 17. Howard PH. Global seed industry changes since 2013. takes decades”,3 and Bayer insists that useful crops can 2017;355(6326):698-700. doi:10.1126/science.aal4222 Philip H. Howard. Published December 31, 2018. Accessed December 4, 2020. https://philhoward.net/2018/12/31/ be developed “in a fraction 9. Wagner JK. Disputes continue over foundational global-seed-industry-changes-since-2013/ of the time compared to older methods”.4 patents for gene editing. The Privacy Report. Published online April 18, 2017. Accessed January 12, 2021. https:// theprivacyreport.com/2017/04/18/disputes-continue- The companies often suggest it is onerous regulations that hold back what over-foundational-patents-for-gene-editing/ would otherwise be rapidly introduced gene-edited products. Corteva argues that “treating CRISPR- produced crops as GMOs would substantially slow down their path to market and adoption of CRISPR innovation in agriculture.”3

48 49 However, while breeding a new plant variety is Gene-edited plants generally a lengthy process, there is no evidence UNIMPRESSIVE RECORD that producing a viable gene-edited variety will be need to go through a any quicker. Even in countries with light-touch While gene editing is 2004. The same is true of a commercialisation. The gene- regulations like the US and Canada, only very laborious process of presented as a cutting-edge non-browning mushroom, edited tomato approved by few gene-edited products have made it to market. screen ing, selection and new technology, it has actually engineered with CRISPR/ the Japanese government has A gene-edited tomato approved by the Japanese been around for some years. In Cas,17 as well numerous not yet been commercialised, government in 2020, which was engineered to backcrossing with the 2012, Jennifer Doudna reportedly due to food contain a compound said to lower blood pressure, parent lines to remove and Emmanuelle To date, only two producers shying away took 15 years to develop.5 That is the same time Charpentier proposed from the technology in period that experts estimate is needed to develop a any obvious undesired that CRISPR could be gene-edited plants the face of consumer sexually propagated non-GM crop – or an older- used for programmable have made it to rejection. A survey of style transgenic GM crop.6,7,8 mutations editing of genomes9 about 10,000 people by and it was first shown market – neither the University of Tokyo to work in plants in found that 40% to 50% 2013.10 The editing tool of which were did not want to eat gene- PROCESS FOLLOWING later named TALENs engineered using edited crops or animal was described in 2009– products, with just 10% THE “EDIT” TAKES TIME 2010.11,12 Regarding the much-touted showing interest in trying 5 As shown in chapter 2, gene editing and its crops engineered CRISPR technology them. associated processes (such as tissue culture) lead with the editing tool to many unintended effects, some of which will called oligonucleotide‐ This record suggests that affect plant performance and growth as well as directed mutagenesis (ODM), other products. According to gene editing is not the efficient 13 the desired trait. So gene-edited plants need to maize was described in 2000 Testbiotech, and speedy route to obtaining 14 go through a laborious process of screening, and rice in 2004. “around 80 plants developed successful agricultural traits selection and backcrossing with the parent lines with new GE techniques have that to remove any obvious undesired mutations. Yet to date, despite the been deregulated by the US is permissive egulatory systems FDA”.18 In addition, several years of greenhouse and in place in North and South Consumer and food industry 15 field trials must be done to ensure that the America, only two gene- mistrust of gene-edited desired trait expresses in a stable way through edited plants have made it to foods is also a the generations and that the plant copes with market – neither of which delaying factor in environmental stresses, such as bad weather were engineered using conditions and pest attacks. the much-touted CRISPR technology. These are Calyxt’s Moreover, genetically modified products are altered-fat-profile soybean, 16 normally only placed on the market once engineered with TALENs, patents are granted – and the patenting process and Cibus’ herbicide- can take years. This means the overall process tolerant canola/oilseed rape, before products can be commercialised can be engineered with ODM. 13 14 lengthy. The ODM maize and rice do not appear to have been All this is without the time needed to put the commercialised anywhere plant through regulatory processes. in the years since they were announced in 2000 and

50 51 claimed. The unimpressive record of products For example, while research on gene-edited 3. Corteva Agriscience. CRISPR Q&A – For internal 14. Okuzaki A, Toriyama K. Chimeric RNA/DNA use only. Published online May 28, 2019. https:// oligonucleotide-directed gene targeting in rice. Plant Cell brought to market in countries like the US saline-tolerant crops struggles to progress crispr.corteva.com/wp-content/uploads/2019/05/ Rep. 2004;22(7):509-512. doi:10.1007/s00299-003-0698-2 and Canada shows that it is not regulations beyond the early stages,19 farmers in India have FINAL_For-Internal-Use-Only_Corteva-CRISPR-QA- UPDATED-5.28.19.pdf 15. Genetic Literacy Project. Global Gene Editing that slow market access, rapidly and successfully Regulation Tracker: Human and Agriculture Gene but factors inherent remediated soil that 4. Tremblay B. Smart and sustainable food systems. Editing: Regulations and Index. Global Gene Editing In the meantime Politico. Published online December 9, 2020. Regulation Tracker. Published 2020. Accessed December in the development of was made saline by a Accessed January 13, 2021. https://www.politico.eu/ 12, 2020. https://crispr-gene-editing-regs-tracker. GM products, as well as solutions have devastating tsunami. sponsored-content/smart-and-sustainable-food-systems/ geneticliteracyproject.org market rejection. The key was found in 5. Asanuma N, Ozaki T. Japan approves gene-edited 16. Calyxt. Calyxt’s high oleic low linolenic soybean already been found organic soil regeneration “super tomato”. But will anyone eat it? Nikkei Asia. deemed non-regulated by USDA. calyxt.com. Published Published online December 12, 2020. Accessed January June 3, 2020. Accessed December 12, 2020. https://calyxt. During the 20 years that to problems such as methods and local 14, 2021. https://asia.nikkei.com/Business/Science/ com/calyxts-high-oleic-low-linolenic-soybean-deemed- gene editing has existed, seeds adapted to the Japan-approves-gene-edited-super-tomato.-But-will- non-regulated-by-usda/ anyone-eat-it there has been much extreme weather conditions.20 17. Waltz E. Gene-edited CRISPR mushroom escapes 6. Goodman MM. New sources of germplasm: Lines, US regulation. Nature. 2016;532(7599). Accessed July 6, research activity – often transgenes, and breeders. In: Martinez JM, ed. Memoria 2018. https://www.nature.com/news/gene-edited-crispr- generously funded with conditions linked to Also, conventional Congresso Nacional de Fitogenetica. ; 2002:28-41. mushroom-escapes-us-regulation-1.19754 taxpayer money – but climate change breeding has consistently 7. Goodman MM, Carson ML. Reality vs. myth: Corn 18. Testbiotech. New genetic engineering: Confusion very few marketable outstripped genetic breeding, exotics, and genetic engineering. In: Proc. of about method of plant identification. Testbiotech.org. the 55th Annual Corn & Sorghum Research Conference. Published September 11, 2020. Accessed January 14, 2021. products. In the engineering techniques Vol 55. ; 2000:149-172. https://www.testbiotech.org/node/2634 meantime solutions have already been found to (old and new) in producing crops tolerant to 8. GMWatch. Is GM quicker than conventional 19. Zhang A, Liu Y, Wang F, et al. Enhanced rice salinity problems such as extreme weather conditions stresses such as drought,21 floods,22 pests,23 and breeding? GMWatch.org. Published December 23, tolerance via CRISPR/Cas9-targeted mutagenesis of the linked to climate change. These solutions rely diseases.24 For more examples of successful 2013. http://www.gmwatch.org/index.php/news/ OsRR22 gene. Mol Breeding. 2019;39(3):47. doi:10.1007/ archive/2013-2/15227 s11032-019-0954-y on already proven and available approaches. alternatives to GM approaches, see chapter 8. 9. Doudna JA, Sternberg SH. A Crack in Creation: Gene 20. Samuel J. Organic farming in India points the way Editing and the Unthinkable Power to Control Evolution. to sustainable agriculture. Inter Press Service. Published Houghton Mifflin Harcourt; 2017. online January 7, 2015. Accessed December 18, 2020. http://www.ipsnews.net/2015/01/organic-farming-in- 10. Jiang W, Zhou H, Bi H, Fromm M, Yang B, Weeks india-points-the-way-to-sustainable-agriculture/ IS SPEED DESIRABLE? DP. Demonstration of CRISPR/Cas9/sgRNA-mediated targeted gene modification in Arabidopsis, tobacco, 21. GMWatch. Non-GM successes: Drought tolerance. sorghum and rice. Nucleic Acids Res. 2013;41(20):e188. GMWatch.org. Published 2020. https://gmwatch.org/en/ Speed in bringing new products to market and primary concern is a safe, wholesome, and doi:10.1093/nar/gkt780 drought-tolerance fast replacement of products is a business model accessible food supply. 11. Boch J, Scholze H, Schornack S, et al. Breaking 22. GMWatch. Non-GM successes: Flood that is interesting for some seed/agrochemical the code of DNA binding specificity of TAL-type III tolerance. GMWatch.org. Published 2020. Accessed In cases where speed is important, gene editing effectors. Science. 2009;326(5959):1509-1512. doi:10.1126/ December 18, 2020. https://www.gmwatch.org/en/ companies and livestock breeders, but less science.1178811 non-gm-successes-flood-tolerance is not the quickest or most reliable way to relevant for farmers, who may be better served produce crops with desired traits. In contrast, 12. Boch J, Bonas U. Xanthomonas AvrBs3 family- 23. GMWatch. Non-GM successes: Pest resistance. with robust, locally adapted varieties and breeds type III effectors: Discovery and function. Annu GMWatch.org. Published 2020. https://www.gmwatch. conventional breeding has proven highly that they can use over a long timespan. In Rev Phytopathol. 2010;48(1):419-436. doi:10.1146/ org/en/pest-resistance efficient and successful in producing such crops. annurev-phyto-080508-081936 addition, it does not serve consumers, whose 24. GMWatch. Non-GM successes: Disease resistance. 13. Zhu T, Mettenburg K, Peterson DJ, Tagliani L, GMWatch.org. Published 2020. Accessed December 18, Baszczynski CL. Engineering herbicide-resistant 2020. https://www.gmwatch.org/en/disease-resistance maize using chimeric RNA/DNA oligonucleotides. Nat Biotechnol. 2000;18(5):555-558. doi:10.1038/75435 REFERENCES

1. International Seed Federation. Technological 2. Euroseeds. Position: Plant Breeding Innovation. advances drive innovation in plant breeding to create Euroseeds; 2018. https://www.euroseeds.eu/app/ new varieties. worldseed.org. Published 2020. Accessed uploads/2019/07/18.1010-Euroseeds-PBI-Position-1.pdf December 8, 2020. https://www.worldseed.org/ our-work/plant-breeding/plant-breeding-innovation/

52 53 8. Gene editing is a risky and expensive distraction from proven successful solutions to food and farming problems

MYTH Gene editing is necessary REALITY to grow food that is “miss out Industry We need to scale up on one of the most better for people and lobbyists claim promising innovations of our proven successful solutions that the use of gene editing the environment, so not lifetime to enable more sustainable resilient is of “unprecedented importance” to deal with – conventional breeding and food systems”.4 applying it would be climate change and scarcity of natural resources agroecology – from which such as arable land and water. They say it is morally reprehensible. necessary to develop crops that are pest- and genetic engineering is an disease-resistant and can adapt to difficult Bayer says the EU expensive distraction. climatic conditions such as drought, heat, and could “miss out on one salinity.1,2 of the most promising According to Bayer, gene editing is innovations of our “fundamental in achieving the goals of the EU Green Deal”3 that aims to tackle both lifetime to enable more climate change and environmental degradation and make the EU economy sustainable. The sustainable resilient company says that if the EU fails to “reverse food systems’’. legislation” that blocks gene editing, it could:

54 55 The EU seed industry association, which Bayer Such arguments create a context in which In the UK, Rothamsted Research’s so-called Ironically, previous government-funded is part of, says it is the EU’s “prohibitive” GMO genetic engineering is viewed as the moral “whiffy wheat” trial, in which wheat was research undertaken by Rothamsted and laws that prevent innovation “for a more imperative – and rejection, or even just genetically engineered to release an aphid- others demonstrated that aphid levels can be sustainable agri-food system at the pace that is regulation, as morally reprehensible. repelling chemical found in mint, failed after kept below economically significant levels urgently needed”.1 £2.6 million of public money was spent on by maintaining diverse field margins and the project. The aphids rapidly got used to the hedgerows.21 This innovative research was smell.20 based on an understanding of agroecology. NEW TECHNIQUES, OLD CLAIMS But seemingly, it has been ignored by GM researchers and their institutions.

Claims that genetic engineering can help The claim of reduced pesticide use also proved farmers to deal with adverse conditions and to be false Herbicide-tolerant GM crops are sold protect the environment are not new. by agrichemical companies in tandem with their CONVENTIONAL BREEDING AND GOOD First-generation transgenic GM crops were proprietary herbicides. They have increased the promoted on the basis of claims that they would use of chemical weedkillers, including products FARMING PRACTICES WORK BETTER be adapted to difficult containing the TO FIGHT PLANT DISEASES climatic conditions, Herbicide-tolerant “probable carcinogen” such as drought, and glyphosate.8,9 Seed industry associations say that gene editing “rust-resistant varieties now cover more than reduce pesticide use.5 GM crops are sold is a way to fight plant diseases while reducing 90% of the wheat farming area in Kenya and Insecticide-producing by agrichemical pesticide use. One promotional video claims Ethiopia”.28 These promises GM crops (so-called that wheat can be proved false. companies in tandem Bt crops) rapidly gene edited to make Attempts to achieve Regarding drought, lost effectiveness The key to controlling it resistant to rust disease resistance a transgenic GM with their proprietary against targeted and powdery mildew both crop diseases through gene editing drought-tolerant pests, fell victim to herbicides diseases.22 are unlikely to match maize from Monsanto Bt toxin-resistant and insect pests lies in these conventional was released in 2011, but the US Department and secondary pests, and are now However, powdery breeding successes. of Agriculture (USDA) said it was no more used in combination with chemical prevention through mildew-resistant Disease-causing effective than conventionally bred varieties.6 insecticides.10,11,12,13,14,15,16,17,18 These include wheat has already good farming practices microorganisms, like Farmer adoption of varieties in which the highly toxic neonicotinoid insecticidal seed been developed insect pests, have drought tolerance was achieved via GM has treatments, the use of which has risen in parallel through conventional breeding, helped by great genetic diversity and thus adaptability, “lagged behind” varieties in which it was with Bt crops in the USA.16 marker assisted selection.23 Progress has been so they can easily “break” a resistance based on achieved by conventional breeding.7 made in gene mapping for powdery mildew changes in one or a few genes. resistance in wheat, to help breeders who want to use these techniques.24 Moreover, the key to controlling both crop GENE EDITING APPROACHES diseases and insect pests lies in prevention Rust-resistant wheat varieties have also been through good farming practices such as crop TO PEST CONTROL SET TO FAIL developed via conventional breeding.25,26,27 rotation,29 which is often ignored in monocrop, According to the International Maize and industrialised agriculture. Agricultural biotech companies are promoting However, these approaches may meet the same Wheat Improvement Center (CIMMYT), its the newer techniques of gene editing as a way to fate as older-style GM crops – as pests can rapidly manage insect pests that would reduce the need evolve resistance to environmental stresses, for chemical insecticides. Proposed approaches whether they consist of sprayed-on chemical include altering plant composition in order to pesticides, built-in pesticides like Bt toxins, or repel pests.19 plants genetically engineered to repel pests.

56 57 laboratory, could have led to “the development Currently, so-called gene drives, a particular GENE EDITING CANNOT CONFER of a truly pathogenic novel virus”, according application of gene-editing technology, are DESIRABLE COMPLEX TRAITS to the researchers.36 The lead researcher being promoted as a way to eradicate insect questioned on Twitter whether this was a “risk” pests.19 But the risks posed by gene drives Conventional breeding continues to outstrip characterised by genetically simple traits, such as worth taking in fields. Meanwhile, non-GM are unpredictable and the impacts potentially 37 GM in developing crops with durable resistance or herbicide tolerance, or modified composition programmes for breeding and supplying virus- severe. to pests and diseases, drought tolerance, to increase product shelf life or provide raw resistant cassava have proven successful over 33 enhanced nutritional quality, and tolerance materials for processing industries.34 These many years, but struggle for funding. to salinity.30,31,32,33 This is because these are traits do not improve the sustainability or genetically complex traits, meaning that they climate resilience of agriculture, but allow are the product developers to SYSTEMS, of many genes continue to sell NOT JUST GENES working together in Genetically complex GM seeds with a precisely regulated traits will be extremely agrochemicals When it comes to solving challenges of pests, yields that are competitive with conventional way. Such traits will and help industry diseases, or climate change, it is crucial to systems after a 5-year transition period. Yields be extremely difficult difficult or impossible to to optimize its look at whole farming systems rather than in the organic systems were up to 40% higher or impossible achieve by manipulating manufacturing employing a reductionist approach that only in times of drought. The trial also found that to achieve by processes. looks at genes, especially genetic engineering organic systems use 45% less energy and release manipulating one one or a few genes approaches that 40% fewer carbon or a few genes, It is not surprising, only manipulate emissions. Crop which is all that gene then, that thus far one or a few genes. Agroecology projects rotations were used editing and genetic modification in general can the only gene-edited crops that have made it As well as robust in the Global South and instead of pesticides to achieve, even using multiplex approaches. to market are Calyxt’s soybean and Cibus’ SU crops providing control pests.38 Canola. The soybean has an altered fat profile stable yields under other developing regions GM has largely succeeded only in producing to avoid creating unhealthy trans fats when adverse conditions, • The System of 35 crops with genetically simple traits such cooking food at high temperatures. The we need resilient have produced dramatic Rice Intensification as herbicide tolerance or the ability to canola has been engineered to enable increased farming systems increases in yields and (SRI). SRI is an express an insecticide. Gene editing is set to herbicide use without killing the crop – the that cope with agroecological method continue on the same path. The gene-edited opposite to the claimed reductions in pesticide a variety of food security of increasing the crops commercialisation pipeline is mainly use from gene-editing technology. environmental productivity of rice by stresses. Such systems include soil building with changing the management of plants, soil, water, organic matter to retain moisture and planting and nutrients. The benefits of SRI include yield GENE EDITING CAN BRING a diversity of crops to prevent pest and disease increases of 20–100%, up to a 90% reduction in problems. the amount of seed required, and water savings ADDITIONAL RISKS of up to 50%.39 Successful systems approaches include : Gene editing plants for disease resistance brings existing natural resistance to a different, more • The organic system. In the longest-running • Agroecology projects in the Global South and other risks, too, some of which have already widespread virus. trial comparing organic and conventional other developing regions. These projects have come to light. Attempts to use CRISPR gene grain cropping systems (including GM crops), produced dramatic increases in yields and food editing to produce virus-resistant cassava plants The experiment also resulted in the propagation the Rodale Institute Farming Systems Trial, security.40,41,42,43,44,45 failed, and in the process broke their already- of mutated viruses that, if they had escaped the researchers found that organic systems produce

58 59 OVER 400 INTERNATIONAL SCIENTISTS REFERENCES

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