The snake with the scorpion’s sting: Novel three-finger toxin sodium channel activators from the venom of the long-glanded blue coral snake (Calliophis bivirgatus)

FWN – Publicaties zonder aanstelling Universiteit Leide

Modern venomics – Current insights, novel methods and future perspectives in biological and applied animal venom research

Venoms have evolved >100 times in all major animal groups, and their components, known as toxins, have been fine-tuned over millions of years into highly effective biochemical weapons. There are many outstanding questions on the evolution of toxin arsenals, such as how venom genes originate, how venom contributes to the fitness of venomous species, and which modifications at the genomic, transcriptomic, and protein level drive their evolution. These questions have received particularly little attention outside of snakes, cone snails, spiders, and scorpions. Venom compounds have further become a source of inspiration for translational research using their diverse bioactivities for various applications. We highlight here recent advances and new strategies in modern venomics and discuss how recent technological innovations and multi-omic methods dramatically improve research on venomous animals. The study of genomes and their modifications through CRISPR and knockdown technologies will increase our understanding of how toxins evolve and which functions they have in the different ontogenetic stages during the development of venomous animals. Mass spectrometry imaging combined with spatial transcriptomics, in situ hybridization techniques, and modern computer tomography gives us further insights into the spatial distribution of toxins in the venom system and the function of the venom apparatus. All these evolutionary and biological insights contribute to more efficiently identify venom compounds, which can then be synthesized or produced in adapted expression systems to test their bioactivity. Finally, we critically discuss recent agrochemical, pharmaceutical, therapeutic, and diagnostic (so-called translational) aspects of venoms from which humans benefit

Modern venomics--Current insights, novel methods, and future perspectives in biological and applied animal venom research

Venoms have evolved >100 times in all major animal groups, and their components, known as toxins, have been fine-tuned over millions of years into highly effective biochemical weapons. There are many outstanding questions on the evolution of toxin arsenals, such as how venom genes originate, how venom contributes to the fitness of venomous species, and which modifications at the genomic, transcriptomic, and protein level drive their evolution. These questions have received particularly little attention outside of snakes, cone snails, spiders, and scorpions. Venom compounds have further become a source of inspiration for translational research using their diverse bioactivities for various applications. We highlight here recent advances and new strategies in modern venomics and discuss how recent technological innovations and multi-omic methods dramatically improve research on venomous animals. The study of genomes and their modifications through CRISPR and knockdown technologies will increase our understanding of how toxins evolve and which functions they have in the different ontogenetic stages during the development of venomous animals. Mass spectrometry imaging combined with spatial transcriptomics, in situ hybridization techniques, and modern computer tomography gives us further insights into the spatial distribution of toxins in the venom system and the function of the venom apparatus. All these evolutionary and biological insights contribute to more efficiently identify venom compounds, which can then be synthesized or produced in adapted expression systems to test their bioactivity. Finally, we critically discuss recent agrochemical, pharmaceutical, therapeutic, and diagnostic (so-called translational) aspects of venoms from which humans benefit.This work is funded by the European Cooperation in Science and Technology (COST, www.cost.eu) and based upon work from the COST Action CA19144 – European Venom Network (EUVEN, see https://euven-network.eu/). This review is an outcome of EUVEN Working Group 2 (“Best practices and innovative tools in venomics”) led by B.M.v.R. As coordinator of the group Animal Venomics until end 2021 at the Institute for Insectbiotechnology, JLU Giessen, B.M.v.R. acknowledges the Centre for Translational Biodiversity Genomics (LOEWE-TBG) in the programme “LOEWE – Landes-Offensive zur Entwicklung Wissenschaftlich-ökonomischer Exzellenz” of Hesse's Ministry of Higher Education, Research, and the Arts. B.M.v.R. and I.K. further acknowledge funding on venom research by the German Science Foundation to B.M.v.R. (DFG RE3454/6-1). A.C., A.V., and G.Z. were supported by the European Union's Horizon 2020 Research and Innovation program through Marie Sklodowska-Curie Individual Fellowships (grant agreements No. A.C.: 896849, A.V.: 841576, and G.Z.: 845674). M.P.I. is supported by the TALENTO Program by the Regional Madrid Government (2018-T1/BIO-11262). T.H.'s venom research is funded by the DFG projects 271522021 and 413120531. L.E. was supported by grant No. 7017-00288 from the Danish Council for Independent Research (Technology and Production Sciences). N.I. acknowledges funding on venom research by the Research Fund of Nevsehir Haci Bektas Veli University (project Nos. ABAP20F28, BAP18F26). M.I.K. and A.P. acknowledge support from GSRT National Research Infrastructure structural funding project INSPIRED (MIS 5002550). G.A. acknowledges support from the Slovenian Research Agency grants P1-0391, J4-8225, and J4-2547. G.G. acknowledges support from the Institute for Medical Research and Occupational Health, Zagreb, Croatia. E.A.B.U. is supported by a Norwegian Research Council FRIPRO-YRT Fellowship No. 287462

How the Toxin got its Toxicity

Venom systems are functional and ecological traits, typically used by one organism to subdue or deter another. A predominant subset of their constituent molecules-"toxins"-share this ecological function and are therefore molecules that mediate interactions between organisms. Such molecules have been referred to as "exochemicals." There has been debate within the field of toxinology concerning the evolutionary pathways leading to the "recruitment" of a gene product for a toxic role within venom. We review these discussions and the evidence interpreted in support of alternate pathways, along with many of the most popular models describing the origin of novel molecular functions in general. We note that such functions may arise with or without gene duplication occurring and are often the consequence of a gene product encountering a novel "environment," i.e., a range of novel partners for molecular interaction. After stressing the distinction between "activity" and "function," we describe in detail the results of a recent study which reconstructed the evolutionary history of a multigene family that has been recruited as a toxin and argue that these results indicate that a pluralistic approach to understanding the origin of novel functions is advantageous. This leads us to recommend that an expansive approach be taken to the definition of "neofunctionalization"-simply the origins of a novel molecular function by any process-and "recruitment"-the "weaponization" of a molecule via the acquisition of a toxic function in venom, by any process. Recruitment does not occur at the molecular level or even at the level of gene expression, but only when a confluence of factors results in the ecological deployment of a physiologically active molecule as a toxin. Subsequent to recruitment, the evolutionary regime of a gene family may shift into a more dynamic form of "birth-and-death." Thus, recruitment leads to a form of "downwards causation," in which a change at the ecological level at which whole organisms interact leads to a change in patterns of evolution at the genomic level

Fossilized Venom: The Unusually Conserved Venom Profiles of Heloderma Species (Beaded Lizards and Gila Monsters)

Research into snake venoms has revealed extensive variation at all taxonomic levels. Lizard venoms, however, have received scant research attention in general, and no studies of intraclade variation in lizard venom composition have been attempted to date. Despite their iconic status and proven usefulness in drug design and discovery, highly venomous helodermatid lizards (gila monsters and beaded lizards) have remained neglected by toxinological research. Proteomic comparisons of venoms of three helodermatid lizards in this study has unravelled an unusual similarity in venom-composition, despite the long evolutionary time (~30 million years) separating H. suspectum from the other two species included in this study (H. exasperatum and H. horridum). Moreover, several genes encoding the major helodermatid toxins appeared to be extremely well-conserved under the influence of negative selection (but with these results regarded as preliminary due to the scarcity of available sequences). While the feeding ecologies of all species of helodermatid lizard are broadly similar, there are significant morphological differences between species, which impact upon relative niche occupation

Squeezers and Leaf-cutters: Differential Diversification and Degeneration of the Venom System in Toxicoferan Reptiles

Radiolog

Modern venomics-Current insights, novel methods, and future perspectives in biological and applied animal venom research.

Venoms have evolved >100 times in all major animal groups, and their components, known as toxins, have been fine-tuned over millions of years into highly effective biochemical weapons. There are many outstanding questions on the evolution of toxin arsenals, such as how venom genes originate, how venom contributes to the fitness of venomous species, and which modifications at the genomic, transcriptomic, and protein level drive their evolution. These questions have received particularly little attention outside of snakes, cone snails, spiders, and scorpions. Venom compounds have further become a source of inspiration for translational research using their diverse bioactivities for various applications. We highlight here recent advances and new strategies in modern venomics and discuss how recent technological innovations and multi-omic methods dramatically improve research on venomous animals. The study of genomes and their modifications through CRISPR and knockdown technologies will increase our understanding of how toxins evolve and which functions they have in the different ontogenetic stages during the development of venomous animals. Mass spectrometry imaging combined with spatial transcriptomics, in situ hybridization techniques, and modern computer tomography gives us further insights into the spatial distribution of toxins in the venom system and the function of the venom apparatus. All these evolutionary and biological insights contribute to more efficiently identify venom compounds, which can then be synthesized or produced in adapted expression systems to test their bioactivity. Finally, we critically discuss recent agrochemical, pharmaceutical, therapeutic, and diagnostic (so-called translational) aspects of venoms from which humans benefit