A 2004 conference in Brazil changed my focus and realized a childhood passion

Authored by Juan Calvete, Biomedicine Institute of Valencia / Global Snakebite Initiative / Spanish National Research Council

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I was born in Valencia, a city on the Spanish Mediterranean coast. From childhood I developed a vocation to know the nature, in particular the fauna, of my environment. During the three months of summer vacations, which I spent with my brothers and cousins half naked and feral among the orange trees of our grandmother’s farm, we hunted lizards, frogs, beetles, grasshoppers, spiders, bats … that inevitably ended their days by revealing their secret anatomy.

After the idyllic stage of high school, I graduated in Biology from the University of Valencia and obtained a PhD in Biochemistry and Molecular Biology from the Complutense University of Madrid, with a Thesis on the structural and biophysical characterization of the human platelet fibrinogen receptor.

Spain is home to several species of snakes, the majority harmless to humans, and the three nominal species of venomous Iberian vipers (genus Vipera) range in mountainous areas and only very rarely produce human envenomings, which when occur generally resolved without the need to administer antivenom. As a consequence, the Spanish herpetological culture is more plagued with popular tales and legends than with scientific and clinical literature. So what motivated me to enter into the field of Molecular Toxinology?

My first experiences with snake venoms date back to the early 1990s, during my first postdoctoral year at MPI fúr Biochemie (Martinsried), when my mentor Agnes Henschen asked me to determine the disulfide bond pattern of a small toxin molecule, disintegrin flavoridin, isolated from P. flavoviridis venom in the laboratory of Stephan Niewiarowski (Temple University). This disintegrin blocks the binding of fibrinogen to its platelet receptor blocking platelet aggregation, impairing clot formation and leading to excessive bleeding. However, the turning point that motivated the change in the direction of my lab’s research, from isolated toxins to venom proteomes and from basic science to applied toxinology, occurred when attending a congress of Pan American Section of the International Society on Toxinology in Angra dos Reis, Brazil (2004). Listening to the lectures and talking to the attendees, I discovered a reality that I was unaware of: snakebite envenoming, a serious public health issue in many tropical and subtropical rural regions affecting not only the victims but often their entire families, which may enter a cycle of generational poverty that is difficult to break. At that meeting I also learned that in spite of its magnitude, the problem of snakebite envenoming had historically faced a neglect: therapeutic antivenoms were scarce, unaffordable where needed or even unavailable in many regions, and knowledge regarding the identity and pathophysiological actions of the venoms’ toxins was relatively limited. With the conviction that understanding the problem is key to solving it, my research group began to develop proteomics-based platforms for exploring the composition and evolution of snake venoms (“venomics”) and to evaluate the preclinical immunorecognition profile of antivenoms towards homologous and heterologous venoms (“antivenomics”).

Knowledge of the evolutionary ecology of venomous snakes and the identity of the most relevant toxin molecules in the context of a human envenoming, are both key for improving our understanding of the underlying pharmacology, and strategies to improve the efficacy of antivenoms. There is much work to be done. In particular, the specifics of venom variation and its impact in the clinical management of snakebite envenomings remain largely unknown. However, while a certain level of human ophidian accidents is inevitable, through integration and contextualization of evolutionary and ecological venomics and preclinical and clinical toxinology information, we believe a pathway is being forged towards a deeper understanding of the disease and the rational design of strategies to control it reducing its incidence to the level of an ecological problem.