Why the second-generation transgenic crops are not yet available in the market?

The reasons behind the lack of second-generation transgenic crops in the market are explained by reinforcing multidisciplinary approaches, and redefining the concept of target environment.


Introduction
Most studies predict that global food demand of major grain crops will not be accompanied by the necessary increase in yield (Hall and Richards, 2013). Additionally, estimated climate change impacts on agriculture predict yield losses of 8-43% respect to current figures, mainly due to abiotic stresses. The second generation of transgenic crops (SGTC) was projected to mitigate these constraints worldwide. However, SGTC remain unavailable as market products. Here, we present our viewpoint about current limitations and future perspectives.

Main text
The reasons for the absence of SGTC in the market are several but have been essentially divided into two main groups: those related to the bad public perception of genetically modified organisms (GMOs) and those associated directly with technical issues; i.e.
technologies developed in controlled conditions do not behave so well in field trials. Notably, both groups converge in one main reason: SGTC do not represent a universal business.
The first group of reasons generated an almost universal regulatory system, onerous, and time-consuming. This system turned the technology difficult to monetize for seed companies except in very "visible" cases such as herbicide resistance (RR technology) and insect resistance (Bt technology), introduced in many crops and "transgenic-friendly" countries.
"Visibility" and the related monetization are linked to the "universal" nature of the trait, expected to express its effects across all environments with no evident genotype × environment interaction. First-generation biotechnologies can, therefore, be characterized as broad-acre solutions; they ensure the control of a biotic constraint and perform similarly in most environments. By contrast, abiotic constraints are seldom tackled qualitatively (i.e. by one trait of universal effect), because they vary in duration, intensity, and opportunity. These characteristics of abiotic stress, together with the high regulatory cost load of genetically modified (GM) crops, posed important limitations to the SGTC respect to traditional breeding and, in some situations, other technologies such as gene-editing. Gene-editing may provide for a faster and less onerous path to market, particularly in GM-friendly countries such as Argentina and the USA, where gene-edited seeds have already been cleared for commercialization (ISAAA, 2019;Whelan et al., 2020). However, this regulatory advantage may not apply to seeds that require multiple modified alleles (mentioned quantitative traits), as gene-edited products are generally analyzed on a case-by-case basis. Also, in less amicable jurisdictions, like the EU, gene-edited crops can be subjected to rigorous and costly risk assessment requirements, just like GMs.
A c c e p t e d M a n u s c r i p t A recent review proposed several options, consistent with sound scientific principles, to reform the EU legislation about GM crops (Eriksson et al., 2020). Push for unambiguous legislation is fueled by restrictive rulings of EU courts on previously unregulated products, such as those derived from targeted mutagenesis. Authors documented the connection of such obstacles with an overall reduction in innovation level and proposed several alternatives, generally based on the principle that risk-assessment requirements must be associated with the phenotypic traits of the new plant and its products, and not with the technique used to obtain them (Eriksson et al., 2020).
We will not refer here to the regulatory problem (for details, see Ayala et al., 2019;Chiozza et al., 2020). Assuming that bad public perception could be solved (or ignored), we will focus on the non-universal nature of abiotic stresses and will analyze why SGTC did not achieve the expected robustness in their response to some of the mentioned constraints.
There is an enormous quantity of scientific literature in prestigious journals devoted to different aspects of Plant Biology in which different genes, inserted in varied genetic constructs bearing constitutive, and later, inducible promoters were tested for stress tolerance. This limitation is many times enhanced by the lack of the necessary interdisciplinary work that the production of SGTC requires (Box 2). Molecular biologists, biotechnologists, and ecophysiologists frequently do their work in an isolated way while ignoring the contribution of colleagues from different areas, including the social ones.
The consequence of such lack of interdisciplinary approach is the costly biotechnological research devoted to the verification of inexistent risks/situations, many times accompanied by poor research protocols to solve the actual problem of the type described for salinity. Protocol weaknesses are typical of the Biotechnology area, where controlled conditions prevail with respect to research based on real soils and photo-thermal conditions representative of a target region. Such inconsistencies can be solved by strengthening the interaction among scientists and farmers from the very early stages of technology development (Fischer and Connor, 2018), which will reduce the risk of mis-constructed science and increase the probability of real-world impact (Sadras et al., 2020).
The use of ancient cultivars stems from the fact that most modern ones are not amenable to transformation. Ancient cultivars show improvements by the presence of a certain transgene, but, the improvement becomes less visible or, directly disappears, once inserted in the genetic background of modern cultivars. However, when repeated field trials were carried out even with such ancient cultivars and showed good results, the chances of success after The lack of interdisciplinary work plays a negative role in science and technology progress. This problem is boosted by scientific journals, which are predominantly representative of A c c e p t e d M a n u s c r i p t close communities (Box 2) and follow certain codes, which may differ markedly in critical issues (as statistical approaches) as well as in less relevant details (as an illustration of results). Efforts and interests of scientists related to SGTC (biotechnologists, molecular biologists, agronomists, breeders, etc.) do not converge naturally, being the "pipeline" of the most important international seed companies probably the only exception to this trend. By contrast, this restriction is almost the rule in the academic world, contributing to the absence of SGTC in the market.

Conclusions
Despite the relative importance of mentioned drawbacks that explain the absence of SGTC in the market, the most critical issue to overcome is the misconception of drought, flooding, or salinity as universal stressors, which led to the search of "the universal winner" (i.e. a single phenotype to cope with them). Abiotic stress varies in opportunity, intensity, and extension as well as in the affected process/es, demanding as many traits and genotypes as the number of possible scenarios. The imprecise prognosis of abiotic stress effects does not allow seed companies to quantify as precisely as intended the expected benefits in yield. Therefore, there is no "clear business" for SGTC. Such putative drought-tolerant plants have a target region where they may bring a (most probably modest) yield advantage to make the technology cashable in years of water shortage, but may represent an additional cost in years with no (or even mild) water constraint.
This situation will not change if seed companies and governments do not accept that benefits can be enormous, provided the concept of target environment is redefined which requires increasing efforts and investment in environment characterization (i.e. soils and climate).
As scientists working in public institutions, we are far away from the decision taken by international companies. Such companies usually interact with public institutions to perform part of their experimental projects, but rarely along the whole pipeline. However, we, as scientists in this discipline, can move closer to small companies and boards of public institutions and governments, aiming at advising on how important innovation is and how critical is to adapt legislation to science in GM and edited crops' subjects. Being optimistic and realistic at the same time, such actions can help to speed up the release to the market of crops improved by genetic engineering techniques, even though they are aimed at limited regions. Benefits for target farmers can be achieved and must not be disregarded because they can lead to benefits for one or more countries, albeit not for all. Downloaded from https://academic.oup.com/jxb/advance-article/doi/10.1093/jxb/eraa415/5913240 by guest on 05 October 2020 A c c e p t e d M a n u s c r i p t