Modernizing and harmonizing regulatory data requirements for genetically modified crops-perspectives from a workshop.

Genetically modified (GM) crops that have been engineered to express transgenes have been in commercial use since 1995 and are annually grown on 200 million hectares globally. These crops have provided documented benefits to food security, rural economies, and the environment, with no substantiated case of food, feed, or environmental harm attributable to cultivation or consumption. Despite this extensive history of advantages and safety, the level of regulatory scrutiny has continually increased, placing undue burdens on regulators, developers, and society, while reinforcing consumer distrust of the technology. CropLife International held a workshop at the 16th International Society of Biosafety Research (ISBR) Symposium to examine the scientific basis for modernizing global regulatory frameworks for GM crops. Participants represented a spectrum of global stakeholders, including academic researchers, GM crop developers, regulatory consultants, and regulators. Concurrently examining the considerations of food and feed safety, along with environmental safety, for GM crops, the workshop presented recommendations for a core set of data that should always be considered, and supplementary (i.e., conditional) data that would be warranted only on a case-by-case basis to address specific plausible hypotheses of harm. Then, using a case-study involving a hypothetical GM maize event expressing two familiar traits (insect protection and herbicide tolerance), participants were asked to consider these recommendations and discuss if any additional data might be warranted to support a science-based risk assessment or for regulatory decision-making. The discussions during the workshop highlighted that the set of data to address the food, feed, and environmental safety of the hypothetical GM maize, in relation to a conventional comparator, could be modernized compared to current global regulatory requirements. If these scientific approaches to modernize data packages for GM crop regulation were adopted globally, GM crops could be commercialized in a more timely manner, thereby enabling development of more diverse GM traits to benefit growers, consumers, and the environment.

Introduction and scientific justification of data transportability for confined field testing for the ERA of GM plants.

The concept of Data Transportability (DT) of Confined Field Testing (CFT) to support the Environmental Risk Assessment (ERA) of Genetically Modified (GM) plants was first introduced in the literature by Garcia-Alonso et al., in 2014. Since then, DT has been discussed in many countries and regions as a concept to prevent duplication of regulatory studies without compromising quality of the ERA. However, despite its usefulness and scientific justification, DT is not well adopted at this time and many regulatory agencies around the world require additional in-country CFT be conducted before approving GM plants. Based on the current circumstances, the authors organized a parallel session entitled "Introduction and Scientific Justification of DT for CFT for the ERA of GM plants" at 16th ISBR (the International Society for Biosafety Research). This session mainly consisted of the following three parts. The first two speakers, Andrew Roberts and Abigail Simmons provided an overview of DT and examples of conditions for the transportability of field data/conclusions advocated in the peer-reviewed scientific journals. Next, the current status of DT adoption in some countries/regions such as Japan and Africa, and a theoretical case study for Argentina were introduced by Kazuyuki Hiratsuka, Douglas Miano, and Facundo Vesprini, respectively. Lastly, a risk hypothesis-based approach for DT which was developed in advance by the five speakers of this parallel session, was introduced. During the discussion, there was a common understanding that transition to the risk hypothesis-based approach for DT was scientifically appropriate, considering the accumulated evidences that several countries have conducted confirmatory local CFT for more than 20 years but they have not detected any differences related to the ERA assessment endpoints in GM crops. The risk hypothesis-based approach for DT introduced here is expected to play an important role in discussions on the implementation of DT in various parts of the world in the future.

Mass spectrometric analysis of digesta does not improve the allergenicity assessment of GM crops.

An investigation of the potential allergenicity of newly expressed proteins in genetically modified (GM) crops comprises part of the assessment of GM crop safety. However, allergenicity is not completely predictable from a definitive assay result or set of protein characteristics, and scientific opinions regarding the data that should be used to assess allergenicity are continuously evolving. Early studies supported a correlation between the stability of a protein exposed to digestive enzymes such as pepsin and the protein's status as a potential allergen, but over time the conclusions of these earlier studies were not confirmed. Nonetheless, many regulatory authorities, including the European Food Safety Authority (EFSA), continue to require digestibility analyses as a component of GM crop risk assessments. Moreover, EFSA has recently investigated the use of mass spectrometry (MS), to make digestion assays more predictive of allergy risk, because it can detect and identify small undigested peptides. However, the utility of MS is questionable in this context, since known allergenic peptides are unlikely to exist in protein candidates intended for commercial development. These protein candidates are pre-screened by the same bioinformatics processes that are normally used to identify MS targets. Therefore, MS is not a standalone allergen identification method and also cannot be used to predict previously unknown allergenic epitopes. Thus, the suggested application of MS for analysis of digesta does not improve the poor predictive power of digestion assays in identifying allergenic risk.

Stem-cell-ubiquitous genes spatiotemporally coordinate division through regulation of stem-cell-specific gene networks.

Stem cells are responsible for generating all of the differentiated cells, tissues, and organs in a multicellular organism and, thus, play a crucial role in cell renewal, regeneration, and organization. A number of stem cell type-specific genes have a known role in stem cell maintenance, identity, and/or division. Yet, how genes expressed across different stem cell types, referred to here as stem-cell-ubiquitous genes, contribute to stem cell regulation is less understood. Here, we find that, in the Arabidopsis root, a stem-cell-ubiquitous gene, TESMIN-LIKE CXC2 (TCX2), controls stem cell division by regulating stem cell-type specific networks. Development of a mathematical model of TCX2 expression allows us to show that TCX2 orchestrates the coordinated division of different stem cell types. Our results highlight that genes expressed across different stem cell types ensure cross-communication among cells, allowing them to divide and develop harmonically together.

SOL1 and SOL2 regulate fate transition and cell divisions in the Arabidopsis stomatal lineage.

In the Arabidopsis stomatal lineage, cells transit through several distinct precursor identities, each characterized by unique cell division behaviors. Flexibility in the duration of these precursor phases enables plants to alter leaf size and stomatal density in response to environmental conditions; however, transitions between phases must be complete and unidirectional to produce functional and correctly patterned stomata. Among direct transcriptional targets of the stomatal initiating factor SPEECHLESS, a pair of genes, SOL1 and SOL2, are required for effective transitions in the lineage. We show that these two genes, which are homologs of the LIN54 DNA-binding components of the mammalian DREAM complex, are expressed in a cell cycle-dependent manner and regulate cell fate and division properties in the self-renewing early lineage. In the terminal division of the stomatal lineage, however, these two proteins appear to act in opposition to their closest paralog, TSO1, revealing complexity in the gene family that may enable customization of cell divisions in coordination with development.

Transcriptional control of cell fate in the stomatal lineage.

The Arabidopsis stomatal lineage is a microcosm of development; it undergoes selection of precursor cells, asymmetric and stem cell-like divisions, cell commitment and finally, acquisition of terminal cell fates. Recent transcriptomic approaches revealed major shifts in gene expression accompanying each fate transition, and mechanistic analysis of key bHLH transcription factors, along with mathematical modeling, has begun to unravel how these major shifts are coordinated. In addition, stomatal initiation is proving to be a tractable model for defining the genetic and epigenetic basis of stable cell identities and for understanding the integration of environmental responses into developmental programs.