Do GMOs Accumulate Formaldehyde and Disrupt Molecular Systems Equilibria? Systems Biology May Provide Answers

Abstract

Safety assessment of genetically modified organisms (GMOs) is a contentious topic. Proponents of GMOs assert that GMOs are safe since the FDA's policy of substantial equivalence considers GMOs "equivalent" to their non-GMO counterparts, and argue that genetic modification (GM) is simply an extension of a "natural" process of plant breeding, a form of "genetic modification", though done over longer time scales. Anti-GMO activists counter that GMOs are unsafe since substantial equivalence is unscientific and outdated since it originates in the 1970s to assess safety of medical devices, which are not comparable to the complexity of biological systems, and contend that targeted GM is not plant breeding. The heart of the debate appears to be on the methodology used to determine criteria for substantial equivalence. Systems biology, which aims to understand complexity of the whole organism, as a system, rather than just studying its parts in a reductionist manner, may provide a framework to determine appropriate criteria, as it recognizes that GM, small or large, may affect emergent properties of the whole system. Herein, a promising computational systems biology method couples known perturbations on five biomolecules caused by the CP4 EPSPS GM of Glycine max L. (soybean), with an integrative model of C1 metabolism and oxidative stress (two molecular systems critical to plant function). The results predict significant accumulation of formaldehyde and concomitant depletion of glutathione in the GMO, suggesting how a "small" and single GM creates "large" and systemic perturbations to molecular systems equilibria. Regulatory agencies, currently reviewing rules for GMO safety, may wish to adopt a systems biology approach using a combination of in silico, computational methods used herein, and subsequent targeted experimental in vitro and in vivo designs, to develop a systems understanding of "equivalence" using biomarkers, such as formaldehyde and glutathione, which predict metabolic disruptions, towards modernizing the safety assessment of GMOs.

EFSA scientific advice to EC on new scientific information in relation to the risk assessment of genetically modified organisms

“…This technical report is the response to a mandate from the European Commission (EC) to evaluate scientific issues raised by a recent publication by Ayyadurai and Deonikar (2015) 1 . By applying systems biology and using a computational model, the authors predicted that a significant accumulation of formaldehyde and concomitant depletion of glutathione might occur in Roundup Ready soybeans due to the genetic modification.…”

“…The EC mandate to analyse the publication made by Ayyadurai and Deonikar (2015) was received on 4 August 2015 (Ayyadurai and Deonikar, 2015). The timeline for receiving EFSA's reply was originally indicated as mid-September 2015, and upon agreement extended to 31 October 2015.…”

“…EFSA was mandated 2 by the EC to evaluate scientific issues raised by a recent publication by Ayyadurai and Deonikar (2015) and 'whether or not the new scientific report will lead to reconsider the outcome of its previous opinions for GMOs '. By using a computational systems biology model, the authors predicted that a significant accumulation of formaldehyde and concomitant depletion of glutathione might occur in Roundup Ready soybeans due to the genetic modification.…”

“…The EFSA assessment described below considers the three main aspects mentioned in the publication by Ayyadurai and Deonikar (2015): (a) the increased levels of formaldehyde, (b) decreased glutathione levels in GM soybeans and (c) the C1 metabolism used in the computer model.…”

“…In delivering this technical report, EFSA considered the data and conclusions reported in the scientific publication by Ayyadurai and Deonikar (2015) 3 along with data in all EPSPS-expressing herbicide tolerant soybean events for which the EFSA GMO panel has already issued a scientific opinion (Table 1). EFSA took into account the appropriate principles described in its guidelines for the food and feed risk assessment of GM plants (EFSA, 2006(EFSA, , 2011a.…”