The question of the origins of snake venom, and three-finger toxins (3FTxs) in particular, has long been a subject that has captivated our team. For years—decades for some of us—we have been deeply immersed in the world of snake venoms, meticulously studying these potent and fascinating substances. 3FTxs, found in cobras in South Asia, Southeast Asia, and sub-Saharan Africa, as well as in kraits in South and Southeast Asia, are crucial components of some of the world’s most medically significant venoms. Without 3FTxs, some of these snakes might become almost non-toxic! These toxins have an enormous impact, disrupting communication between neurons and muscle cells by blocking receptors, leading to paralysis, and contributing significantly to human snakebite mortalities annually.

In our previous work, we developed a specific way to track parts of genes - exons - across genomes. This allowed us to reveal fascinating insights into the evolution of snake venom serine proteases and phospholipases. However, we faced a significant roadblock: the inability to precisely track the evolution of novel structures within these gene families. We were staring at a tantalizing mystery that was just beyond our grasp.

The breakthrough came when we started combining our established methods with the burgeoning capabilities of Artificial Intelligence (AI), including protein language models. Suddenly, it was as if a veil had lifted. Our new perspective, a harmony between human expertise and machine learning power, enabled us to journey back in time to reconstruct the origins of snake venom 3FTxs. Our research reveals that these toxins evolved from a gene—a particular member of Ly6family—that is found ubiquitously in squamate reptiles and is typically membrane-bound. In general, Ly6 play a pivotal role in cell-signalling pathways essential for maintaining bodily health and growth. However, a series of changes, starting around 120 million years ago, set certain copies of Ly6 on a unique evolutionary path.

Our novel integrated approach was so pivotal to the study of 3FTxs that our current findings would have been unattainable a mere 1-2 years ago. We discovered that as these genes duplicated over time, evolving from one species to another, the toxins they produced became increasingly versatile. This increased versatility might have been a critical factor that enabled snakes to diversify and specialize in various ecological niches, increasing the range of prey susceptible to these toxins, or preventing prey animals from evolving resistance.

For the first time ever, we have a comprehensive timeline of the evolution of 3FTxs. This not only provides deep insights into the evolutionary origins of novel functions but may also inform the development of new treatments for snakebites and contribute to advancements in drug development. Recognizing how these toxins function could potentially repurpose them as tools for the benefit of humanity.

Looking ahead, our team is eager to continue this work. We plan to improve our approach to delve deeper into the evolution of various 3FTx subgroups, each with a different target. We are also excited about extending our research methods to study additional toxins in other organisms, including jellyfish, spiders, and poisonous mushrooms. Our collaboration is aimed at deepening our understanding of toxin evolution and shedding light on the intricate roles these molecules play in mediating antagonistic interactions between—and even within—species.

The secrets behind life's deadliest cocktails remain elusive, but each step forward in our journey brings us closer to new scientific breakthroughs. As we look to the future, the blend of enduring curiosity and powerful new tools promises a thrilling continuation of this exploration.