Why do we study animal toxins?

Abstract

Venom (toxins) is an important trait evolved along the evolutionary tree of animals. Our knowledges on venoms, such as their origins and loss, the biological relevance and the coevolutionary patterns with other organisms are greatly helpful in understanding many fundamental biological questions, i.e., the environmental adaptation and survival competition, the evolution shaped development and balance of venoms, and the sophisticated correlations among venom, immunity, body power, intelligence, their genetic basis, inherent association, as well as the cost-benefit and trade-offs of biological economy. Lethal animal envenomation can be found worldwide. However, from foe to friend, toxin studies have led lots of important discoveries and exciting avenues in deciphering and fighting human diseases, including the works awarded the Nobel Prize and lots of key clinic therapeutics. According to our survey, so far, only less than 0.1% of the toxins of the venomous animals in China have been explored. We emphasize on the similarities shared by venom and immune systems, as well as the studies of toxin knowledge-based physiological toxin-like proteins/peptides (TLPs). We propose the natural pairing hypothesis. Evolution links toxins with humans. Our mission is to find out the right natural pairings and interactions of our body elements with toxins, and with endogenous toxin-like molecules. Although, in nature, toxins may endanger human lives, but from a philosophical point of view, knowing them well is an effective way to better understand ourselves. So, this is why we study toxins.

Keywords: Disease mechanism; Drug development; Evolution; Survival competition; Toxins.

Figure 1

Venom (a mixture of toxins) evolved along the evolutionary tree of animal kingdom As a special trait in animal kingdom, venom system has evolved in nature for survival competition, which plays important roles in predation, defense, competition, antimicrobial and even communication in given ecological contexts. The common and well-known venomous animals are shown. Toxins are produced from single cell protozoans to metazoan primates.

Figure 2

Evolutionary diversification of toxins Dobzhansky (1973) stated in a classic article that nothing in biology makes sense, except in the light of evolution. The extensive diversification of toxins may have been driven by extreme diversification of physiological elements of potential preys and predators in evolutionary processes. Toxins may be subject to evolutionary Red Queen Effect (Van Valen, 1974), in which toxins must evolve rapidly to effectively act on diversified biological targets. On the other hand, it is possible that the physiological elements, which are critical for the survival of organisms, have to constantly change them to evade being targeted by toxins.

Figure 3

Contribution of toxins in deciphering human patho-physiology and diseases mechanisms With animal toxins as irreplaceable molecular probes and research tools, many exciting discoveries have been made, which have significant impact on life sciences and medical fields. See description in detail for each story and references cited in the text.

Figure 4

Toxin knowledge guides physiological toxin-like protein/peptide (TLP) study There are numerous TLPs expressed in non-venomous animals and/or in non-venom systems with unknown physiological functions, including those in mammals. Knowledge obtained in the study of toxins has greatly facilitated uncovering the functions and mechanisms involved of these endogenous TLPs. See description in detail for each story and references cited in the text.

Figure 5

Modern toxin-based drugs developed The potency, specificity, and stability of toxins have made them an invaluable source of natural products for drug discovery. The approved and widely used drugs derived from venom peptides or proteins are listed here. See description in detail for each example and references cited in the text. There are still tens of molecules in clinical trials and many more in various stages of preclinical development.

Figure 6

Similarity shared by venom and immune systems The basic similarity of venom and immune systems is reflected by their primary biological tasks, attacks and defenses. The genetic and evolution origin of toxins and immune effectors are believed to evolve via the ‘birth and death’ process of gene evolution (Casewell et al, 2013; Fry, 2005; Nei, 1997). Recruitment of a proper gene and duplication and rapid mutation created diversified innovative toxin or immune effective molecules, which are selectively expressed in the venom glands or immune related organs.

Figure 7

Aerolysin-like proteins (ALPs) and trefoil factors (TFFs) may consist of novel pathways and effectors in immunity. A: βγ-CAT, a heteromeric complex consists of Bm-ALP1 and Bm-TFF3 (a three domain TFF), was identified from Bombina maxima (insert). Upon bacterial infection, pathogen-associated molecular patterns (PAMPs) induce the activation of Toll-like receptors (TLRs), which subsequently trigger the intracellular production of pro-IL-1β. Additionally, βγ-CAT was endocytosed via membrane receptor mediation. Bm-ALP1 was found to oligomerize along endo-lysosome pathways to trigger lysosome destabilization, and led to IL-1β maturation and secretion via inflammasome activation, resulted in host rapid and effective antimicrobial responses (Xiong et al, 2014). B: ALPs mainly contain a pore-forming aerolysin domain that undergoes fusion with agglutinin, jacalin, tachylectin, DM9, βγ-crystallin, and Ig-like domains have been found (Szczesny et al, 2011; Xiang et al, 2014), and could be readily identified by blast in GenBank from diverse plant and animal species, such as rice, grapes, fishes, amphibians, reptiles as well as birds. The schematic domain composition of representative ALPs is cited and modified from Szczesny et al (2011). We speculated that some of these ALPs might be sugar-binding oligomerization proteins (SOPs), which could be regulated by sugar recognition and binding.

Figure 8

Venom systems provide nice models to understand fundamental biological questions

Figure 9

Recognizing us from toxins is an effective way to better understand ourselves. To understand human physiology and diseases, studies in model animals rely on the similarity and conservation shared by humans and model animals in evolution. In nature, toxins are agianst humans, and studies depending on the evolutionary interaction between humans and toxins are an alternative and effective way to better understand ourselves.