A research program for the socioeconomic impacts of gene editing regulation

ABSTRACT

Gene editing technologies are a group of recent innovations in plant breeding using molecular biology, which have in common the capability of introducing a site-directed mutation or deletion in the genome. The first cases of crops improved with these technologies are approaching the market; this has raised an international debate regarding if they should be regulated as genetically modified crops or just as another form of mutagenesis under conventional breeding. This dilemma for policymakers not only entails issues pertaining safety information and legal/regulatory definitions. It also demands borrowing tools developed in the field of social studies of science and technology, as an additional basis for sound decision making.

KEYWORDS:

• agriculture
• biosafety
• GMO regulation
• gene editing
• genetic modification
• innovation
• NBTs
• productive and economic issues
• science and technology

INTRODUCTION

Gene editing technologies (GETs) are a group of recent innovations in plant breeding using molecular biology tools. It is becoming evident that GETs are able to introduce advantageous traits for both the producers and consumers of agroindustrial and agrifood products, into crop varieties that could be commercially available very soon. However, there is still a need of clarifying the regulatory status of crops improved using GETs, particularly in regards to worldwide established regulations on Genetically Engineered or Genetically Modified (GM) crops.

GETs are a subgroup of the so-called “New Breeding Techniques” (NBTs), a term which encompasses many novel techniques in plant breeding using molecular biology tools. Different NBTs have dissimilar prospects on how they may be regulated, as we describe in our article recently published in this journal (Whelan and Lema, 2015). In that article, we reviewed in detail the current regulatory conundrum for NBTs and its current state of play. It focuses on Argentina as the first country that has issued a regulation specifically addressing NBTs based on Cartagena Protocol definitions and customary regulatory criteria for GM crops.

Within NBTs, GETs as a subgroup have in common the possibility of introducing a site-directed mutation or deletion in the genome. This subgroup includes techniques using Site-Directed Nucleases (such as TALEN, ZFN, MNs or CRISPR-CAS9) of type I and II (SDNI and SDNII) as well as Oligonucleotide-directed mutagenesis (ODM) (Lusser and Davies, 2013; Samanta et al., 2016).

Crops modified using GETs raise the question of how these should be regulated (Jones, 2015; Wolt et al., 2016). Some argue that they fall under the umbrella of “modern biotechnology,” as defined in the Cartagena Protocol, and hence they should be regulated as GM crops; conversely, others claim they are just another form of mutagenesis, and thus they should be regulated as conventional crops.

The techniques belonging to the subgroup of GETs are different from each other in the view of biotechnology experts regarding their relative advantages for modifying the plant genome (Wolt et al., 2016). For the purposes of this article, however, we consider them altogether because all of them share the capability of introducing a site-directed mutation or deletion in the genome (other NBTs have different capabilities in regards to the kind of genetic modification they entail). We consider only GETs in this article because they are the ones with higher possibilities of end up being regulated as just another form of human induced mutation within the umbrella of conventional plant breeding.

The regulation imposed over GM crops has shaped how these crops are (or not) developed and used by certain countries, which traits are chosen for commercialization, who benefits from it and the pace of technology adoption from laboratory to the field (De Greef, 2011).

Depending on the decisions that policymakers will take regarding if Gene-Edited Crops (GECs) are GM or conventional crops (or something else), there will be very different scenarios for potential socioeconomic and productive impacts.

As a result, policymakers are receiving input on this issue not only from experts in regulatory affairs, but also views from academia, the industry, the agricultural and trade sectors and non-governmental organizations (NGOs), among others.

As usual for cases like this, policymakers have to balance information from “hard” or “natural” sciences with a changing scenario regarding social attitudes, perceptions and claims (Malyska et al., 2016). Hence, there is a need of embarking on social studies covering complementary aspects of GECs, to inform and assist policy-making activities. While our earlier article in this journal addressed the “regulatory science” or hard aspects, the present article explores how social studies performed while the technology is being developed and adopted by society (referred here as studies “in the making”) could assist decision taking.

Social Studies of Science and Technology

The field of social studies of science and technology (SSCT) is an established but still blooming discipline. It covers how social, political, and cultural factors interplay with scientific research and technological innovation. It is not only a highly interdisciplinary field involving scientists from natural sciences, sociologists, philosophers, economists, etcetera, but also it houses many very different schools and approaches, such as innovation economics, politics of science and technology, sociology of science and innovation, etc.

The discipline began in mid-nineteen century with studies about knowledge dynamics and most renowned authors of this period include Max Scheler and Karl Mannheim, who initiated the study of knowledge from a sociological perspective and began conceiving knowledge as a social product. During the 20^th century, after the 1930´s the discipline entered a new turn with studies addressing the conditions that govern the production of science; Robert Merton (focusing on the role of scientific institutions) or Joseph Ben-David (focusing on the social aspects governing the production and validation of scientific knowledge) are among the reference authors of this period. Following the 1970´s, the discipline turned to the interplay of science and general society, taking into account “technology” also. During that period, the discipline was shaped to its current state of the art by Bruno Latour, David Bloor, Michel Callon, Trevor Pinch, Pierre Bourdieu, Karin Knorr-Cetina, Harry Collins, among others. These authors initiated studies of science “in the making” with new research tools, including methodologies borrowed from ethnology; and ultimately science and technology is modeled as a social construction made by a network of interacting actors. For a detailed review of the evolution of this discipline see the following references (Latour, 1987; Gatica, 2015; Premebida et al., 2011; Shinn, 1999).

Particularly in regards to studies on the economy of innovation, it began the 1940s with the pioneer works by Joseph Schumpetter, who identified innovation as one the mayor causes of economic transformation and development. Then, the field was further fostered by Christopher Freeman, Sydney Winter, Bengt-Åke Lundvall y Charles Edquist inter allia (these authors contributed mostly with empirical studies of innovation systems at company, regional and national levels) (Freeman, 1982; Nelson and Winter, 1982; Lopez; Fagerberg, 2005). It is also relevant to mention the influential reference works by the Organization for Economic Cooperation and Development (OECD) (Oliver et al., 2012) on data gathering (OECD/Eurostat, 2005) and standard research practices (OECD/Eurostat, 2002).

Aspects to be Studied

As mentioned, social studies of science and technology encompass many diverse subjects and approaches that are relevant to different aspects of GETs. Some, for instance, would be applicable to the initial steps of scientific research and the subsequent development of these technologies. However, in this article we are concerned about ongoing policymaking activities related to agricultural applications, where policymakers may need to consider first the regulatory aspects. These aspects include “hard” scientific information on safety of products obtained with GETs, and the pre-existing definitions of regulated articles, as well as the issue of the “adequate level of protection” (Atik, 2011; Sgrillo, 2016). However, especially in regards to the latter, policymakers also have to balance (a) potential social, productive and economic benefits derived from the introduction of GECs and (b) scenarios covering the interplay of the seamless fabric of society with these technologies (Hughes, 1986; Latour, 2003). The latter two issues are those we propose that should be addressed in a first instance by SSCT aimed to result useful for current policymaking efforts.

Prospective Studies on Productive and Economic Impacts

There is plenty of literature describing how GM crops have delivered productive and socioeconomic benefits (Brookes and Barfoot, 2014; ISAAA Annual Report, 2015; European Commission, 2000). But there are also many references covering how the public perception issues and regulatory “burden” (in terms of human and economic resources as well as time) has affected innovation and the adoption of these crops (Phillips, 2014; Bayer et al., 2010; Smyth, 2016), leading to an asymmetric development. For instance, in the Americas there is wide cultivation and applied research on GM crops, while in Europe cultivation and research is scarce.

Since agriculture and food is a global business, another important issue to consider for the release of GM crops is the potential gap from regulatory asynchronies or asymmetries between countries. The commercial release of the GM crop by a single exporting country may complicate international trade if that crop or its derived products are not yet approved overseas. There are plenty of examples of this in the literature, including the World Trade Organization case involving Canada, US and Argentina claiming against the European Communities for the approvals of GMOs (Disdier and Fontagné, 2010).

These conditioning factors have also led to only a handful of multinational companies entering a global market after climbing high regulatory barriers, whose regulatory costs are be amortized in a few years of remaining patent time before expiration (NW., 2013). Not surprisingly, it has been almost impossible so far for GM crops developed by small and medium-sized enterprises (SMEs) or the public sector to reach the market.

For example, the worldwide known “golden rice” case shows how regulatory systems can be decisive for the marketing of a product obtained by modern biotechnology. Golden Rice has been modified to increase the pro-vitamin A content in foods derived from it, and it would be considered a GM crop (or comparable categories of regulated articles for Canada and the US) in any regulatory agency in the world. It was developed in 2003 by the Swiss Federal Institute of Technology and the University of Freiburg with non-profit, humanitarian purposes. Although this product is perfectly safe for eating and cultivation, and despite its huge potential contribution to alleviate public health problems, it has not received a commercial approval yet in target countries like Bangladesh (Regulation, the toughest hurdle so far).

Furthermore, it is enlightening to take a comparative approach regarding how regulatory systems impose a differential burden for conventional versus GM crops, such as the following example from Argentina:

In one hand, a herbicide-resistant (imidazolinone) rice was co-developed by BASF Company and the National Institute of Agricultural Technology (INTA). It was obtained by chemical mutagenesis; as a consequence this crop is considered a product of “conventional breeding” and it does not fall under the regulatory system for GM crops. Therefore, it was released to commercialization in Argentina and other countries shortly after the varieties were obtained, and it is being cultivated successfully by farmers.

The weedy red rice is a subspecies of rice growing wild and considered a weed in Argentina and other countries; it can have as much as 30% intercrossing with commercial rice (Flujo de genes del arroz cultivado ). As a consequence, the herbicide resistance trait is inherited by hybrids between the commercial and the red rice, being these hybrids also considered a weed. In practice, this intercrossing has not translated into a significant problem for the utility of this herbicide-resistant crop or the life cycle of the technology involved. This is because the issue can be solved when growers abide to particular (although non-sophisticated) agronomic practices, consisting on intercalating the use of a different herbicide every three years, to clear the hybrid plants having resistance to imidazolinone (PUITÁ INTA CL; Health Canada).

On the other hand, an ammonium glufosinate tolerant rice was developed long time ago by Bayer Crop Science by plant transformation, and it is considered a GM crop. Although the product has been assessed as a safe source of foodstuff, it has not yet received biosafety clearance for planting in Argentina (as well as in other countries) since GM crop regulators are still considering the theoretical consequences of the herbicide resistance gene being transferred to the weedy red rice (ILSI Research Foundation).

This example shows the impact of regulation on two crops differing only in the technologies applied to breed them. The same species (rice), same trait of herbicide tolerance (even though it is not exactly the same chemical herbicide, this does not matter much for the present comparison), same regulatory system, same potential implications regarding sexually compatible weeds and changes in agricultural practices, but very different outcomes due to the technology used to obtain each.

Considering the lessons from the “ex-post” case above, current state of affairs for GECs is amenable to begin “in the making” studies on the impacts derived from their regulation. The main objective would be to assess if the trajectory of GECs follows the path of “conventional” novel (mutant) crop varieties, or the one of GM crops, or a third path with its own peculiarities. A model case, for instance, could compare:

1. Canola having herbicide tolerance (glufosinate) developed by Bayer Crop Science. This crop was considered a regulated article under the regulatory frameworks usually applied to GM crops in Canada, US and the EU and other six countries. After the corresponding biosafety and food safety assessments, it received approval in all of these countries and it is present in their markets since the year 1997 (Washington (DC): ILSI Research Foundation, 2015).

2. Canola also modified for herbicide tolerance (sulfonilurea). This GEC was developed by the CIBUS company using oligonucleotide directed (or mediated) mutagenesis. In the year 2004 it was regarded as a non-regulated article by the US Department of Agriculture (Wolt et al., 2016), while Canadian authorities have issued an approval in 2013 (DD 2013–100), after a regulatory safety assessment under the novel trait regulation (the one usually applied to GM crops in that country, where the method for obtaining a new trait is not a regulatory trigger) (Macdonald, 2014).

In the EU, there is still uncertainty regarding the regulatory status of NBTs for its Brussels-based centralized system for GMO commercialization approvals. Nevertheless, field trials are managed at the national level, and both the competent authorities of UK and Germany have issued the opinion that this crop is not GM and therefore it does not require prior authorization for performing field trials in their territory (the German decision, however, has been defied by other governmental agencies) (Corporate Europe Observatory, 2016).

The two crops to be compared belong to the same species; although the herbicide used is chemically different this is not significant for the comparison since they would be used for the same agricultural purposes and under equivalent practices. Cibus is about to start growing the crop in the US, Canada and perhaps China (Cibus in the News, 2016). An “in the making” study on the fate of this product (and the Cibus company itself) vis a vis with the trajectory of the Bayer Crop Science canola would be informative regarding the following issues:

• if GECs bear less overall (global) regulatory burden compared to GM crops. And if such advantage is significant in terms of regulatory costs and time from conception of the product to reaching the market. It would be convenient to study separately two stages: from conception to regulation and from regulation to the market. This is because the kind of genetic modification introduced by GECs is simpler, consisting in site directed mutations or deletions in the genome; in contrast, GM crops typically involve a variable number of randomly located insertions of DNA constructs. Therefore, likely the development and breeding process of GECs before regulation is also less costly and time expensive.

• if these time and cost differences for the developer actually cause that equivalent technologies (incorporated in the seed) are available to the farmer sooner and/or with a lesser cost.

• Providing the crop reaches commercialization in countries where GM crop cultivation is now null or scarce, if GECs entail the agricultural sector of that countries to compensate for the competitive advantage of farmers from other regions growing GM crops.

• if the success of the first products obtained through gene editing will encourage the development of agricultural biotechnology products in SMEs and public institutions that so far have encountered difficulties navigating through the costly GMO regulatory system and/or in countries where there has been significant social/political rejection of GM crops.

The basis for such comparative analysis should cover, inter allia, development and regulatory costs for obtaining each herbicide-tolerant crop, time required to reach the market from development to commercial approval, dynamics of farmer adoption and commercialization of derived products, perception from actors not directly involved in decision making and regulatory affairs, such as consumers, farmers, etc. (Ishii and Araki, 2016).

The Cibus/Bayer herbicide-tolerant canola(s) case is depicted here for illustrative purposes, given these crops are worldwide known. However, an increasing number of GECs from different companies are approaching the market and therefore the same analysis could be equally performed on more than one combination of crops and national regulatory systems. Actually, if different researchers would cover more than one case this could help reaching robust and general conclusions, which in turn would be more useful for the harmonization of policy- and decision-making processes.

“Construction” of the Gene-Editing Technologies

As it has been repeatedly stablished in SSCT studies, for many aspects like efficacy or safety of a technology there are not only “hard” aspects implied, but also they are subject to the perspective of diverse social actors regarding what is considered functional or safe. Moreover, this perspective can change along the trajectory or life cycle of a technology (Deeter, 2006). Such societal determination of “what is” and “how good is” a technology constitutes an important part of the “construction” process from a SSCT perspective. Technologies are influenced by alliances from heterogeneous factors that impact in their functionality, and in turn technologies can impact on the viability of socio-economic models; this leads to the concept of socio-technical systems (Smith et al., 2014).

GECs altogether can be considered, from a SSCT perspective, as a single technological artifact. The interplay of society and technological artifacts can be studied using different approaches including Actor-Network Theory (Law, 1992; Latour, 2005; Callon, 1986), Social Construction of Technology (Pinch and Bijker, 1984), or Socio-technical analysis (Whitworth and De Moor, 2009; Thomas et al., 2006). It is important to take into account that, while safety or efficacy of a new crop necessarily needs to be assessed case by case, policies are necessarily made for general application, and thus it is convenient to count with analytical tools that address GECs altogether as a single artifact.

The literature covering studies on social construction of technological artifacts mostly includes “ex post” studies. In contrast, GECs are an excellent model to study “in the making” because at the present time, before the story is over, there is a need of anticipating the creation and positioning of social alliances regarding the artifact. This not only includes, as mentioned, policymakers; it also includes “investors” in a broad sense (decision makers from academic labs to biotech and seeds companies facing the option of using these technologies).

Currently there is still plenty of interpretative flexibility regarding GECs, for instance if they are new varieties obtained by conventional mutation breeding or GM crops (or a third kind of artifact.). But also there is interpretative flexibility in additional aspects, for instance if they represent or not a promise for the development of agricultural biotechnology in countries where nowadays the door is closed to the development and/or cultivation of GM crops. Another aspect would be if they represent a real technical advancement for whichever crop category they fit in.

Also the network of actors is mutating. Initially it only included specialized researchers, later biotech companies and regulators entered it, now policymakers as well as “proBiotech” and “antiBiotech” NGOs are taking stance. In the future the network should expand to include farmers, as well as grain traders, the public and perhaps unexpected actors such as the entertainment industry (American Association for the Advancement of Science, 2016). Even within biotech companies, their differential capabilities of exploiting one or another kind of crop would impact on the alliances they may enter with other social actors to support a certain attitude toward GECs. Companies now are just exploring these capabilities, so they are in a stage of interpretative flexibility at the individual level.

Even analogous actors may display different attitudes across national borders. For instance, in Europe most environmentalist NGOs and policymakers have been very reluctant toward GM crops; in the long-term, this led to academic researchers and seed companies eventually quitting from working with plant genetic engineering, even when it was practically born in Europe (Herrera-Estrella et al., 1983). Perhaps for the same reasons in European there is a high interest in crop improvement using NBTs (Krens et al., 2015; Holme et al., 2013) (if not regulated as GM crops), as an opportunity of bringing biotechnological innovation back to the agricultural sector. Conversely, in countries where GM crops have been widely used safely for over 20 years, the attitudes are less polarized among equivalent actors.

There is plenty of literature covering non-adoption/rejection of artifacts or technological systems, being the most paradigmatic case the Luddite movement at the beginning of the industrial age in the UK. “Resistance” is the term usually used to describe such phenomenon, which usually is more than just rejection of a certain technological artifact. It involves ideological opposition to the “otherness” among socio-technical alliances of actors with differing interests; this opposition is often channeled through constructing a “non-functional” interpretation of the artifact (Thomas, forthcoming).

An example of this can be found in the conventional/GM crops dichotomy: in the beginning most of the “non-functional” rhetorical attacks to GM crops involved questioning their safety, but the accumulation of “hard” scientific evidence and familiarity with the technology made these criticism fade over time. Then, the focus moved to questioning their overall agricultural efficacy; however this second line of argumentation against GM crops is losing ground, and currently most of the non-functional interpretation is based on trade disruption risks derived from asynchronic decisions of national regulatory systems (which are actually a long-term consequence of the first motive of criticism against GM crops).

Conventional breeding, on the other side, has been described by the rival sociotechnical alliance as inefficient or unsustainable for reaching by itself the goal of nurturing the future world demand of agrifood products. The same applies to organic agriculture which, interestingly, seems to have been actually fostered by the commercialization of GM crops (Smyth et al., 2015).

In conclusion, it would be very useful to analyze how these preexisting sociotechnical alliances, which never stopped from mutating actants and evolving interpretations of what is a GM crop, are reconfiguring now in reaction to the rise of GECs.

CONCLUSIONS

GECs having genome mutations/deletions, as a technological artifact, have just begun to be “constructed” by society at the national and global level. “In the making” studies addressing such social construction and the more probable technological trajectories for GECs are much needed, particularly by policymakers and developers to complement “hard” information pertaining safety and performance.

Many lessons are to be applied from the recent, quite established and very close experience with the technological trajectory of the “GM crops” artifact. The results of the case comparisons between GM crops and GECs with the same trait, as proposed here, may result informative mostly in regards to the real possibilities of diversifying the availability of crop species and traits improved by biotechnology (currently limited in most countries to soybean, maize, canola or cotton modified for insect resistance or herbicide tolerance). In addition, it may provide interesting information about opportunities of diversifying and increasing the number of competing suppliers vis-à-vis current concerns for the increasingly high business concentration of this sector (The Washington Post, 2016). For countries where GM crops have encountered more resistance and consequently research and development has been halted, these studies may be informative about how realistic are the possibilities of reopening opportunity for innovation in the seed sector from public research institutions to small and medium-sized seed companies to the farmer.

Of course this could happen with a niche dynamics, leading to differential opportunities for public sector research and seed/biotech SMEs to reach the market with crops of regional importance and traits of local interest. Complementing the latter, multinational companies would be able to deliver sooner their innovations involving crops of widespread cultivation such as soybean or maize and traits that work everywhere such as herbicide resistance or nutritional improvement.

This is an ambitious proposal for a research program whose results are urgently needed by policymakers of many countries. It encompasses several research avenues, which can be explored repeatedly at the light of different national or regional regulatory regimes, different study cases and scenarios, etc.

The purpose of this article is duo fold, in one hand to attract the attention of SSCT researchers to this model of study, since the research program delineated here cannot be encompassed by a single research group for the reasons stated in the paragraph above. In addition, to raise awareness among investors, policymakers and other decision makers that such studies should be requested and taken into consideration when formulating balanced and robust lines of action regarding GECs.

In regards to pioneer social studies to address policymaking on GETs, it is worthwhile to note two ongoing activities at the moment of submitting this article. In one hand, researchers from Saskatchewan University are conducting a survey-based multi-year research project on global risk decision making as it relates to new plant breeding techniques (Stuart Smyth, personal communication). Also, the OECD is about to hold a “Workshop on Gene Editing in an International Context: Scientific, Economic and Social Issues across Sectors” (Steffi Friedrichs, personal communication). Publications from these activities would be much relevant when available.

DISCLAIMER

The information and views are those of the authors as individuals and experts in the field, and do not necessarily represent those of the organizations where they work.

ABBREVIATIONS

CRISPR-CAS9	=	clustered regularly interspaced short palindromic repeats - associated protein-9 nuclease
EU	=	European Union
GECs	=	Gene-Edited Crops
GETs	=	Gene editing technologies
GM	=	genetically modified
MNs	=	Mega Nucleases
NBTs	=	New Breeding Techniques
NGOs	=	Non-governmental organizations
OECD	=	Organization for Economic Cooperation and Development
ODM	=	Oligonucleotide-Directed Mutation
SDN	=	Site –Directed Nucleases
SMEs	=	Small and medium-sized enterprises
SSCT	=	Social studies of science and technology
TALENs	=	TAL Effector Nucleases
US	=	United States
ZFNs	=	Zinc Finger Nucleases

DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST

No potential conflicts of interest were disclosed.