Beyond the static lab: environmental variability in genetically modified mosquito target gene identification for malaria control.

As malaria remains a critical public health challenge, causing hundreds of thousands of deaths annually, novel methods to combat it are urgently needed. Genetically modified mosquitoes (GMMs) offer a promising, innovative approach to reducing malaria transmission. However, the foundational research to identify the target gene candidates for genetic modification is typically conducted under static laboratory conditions. These standardized insectary settings of constant temperature and humidity do not reflect the dynamic environmental and climatic variability that mosquitoes and the pathogens they carry encounter in nature. Here we argue that this 'lab-to-field' discrepancy represents a significant knowledge gap. We highlight that natural variations in environmental factors influence Anopheles and Plasmodium biology, and mosquito innate immunity responses, with consequences for vector competence and malaria transmission. Insufficient consideration of environmental variability during the initial gene discovery phase risks developing GMMs where the intended function of the genetic modification may be compromised by environmental stress. We emphasize the need to incorporate realistic environmental variability into the upstream GMM development, particularly in the face of escalating climate change.