Malevolent Design - Combatting The Highly Toxic, Tissue Destroying Spitting Cobra Venom

African black-necked spitting cobra, Naja nigricollis

Warren Klein via Wikimedia (CC BY-SA 3.0)

Black-necked spitting cobra, Naja nigricollis

© Marius Burger, CC0, via Wikimedia Commons

First effective treatment found for spitting cobra snakebite - Lancaster University

Snake venom is usually a potent cocktail of multiple different toxins, 'designed' to kill, mostly small vertebrate prey very quickly, so the snake can strike, then wait for the prey to become paralyzed or die before it can go very far.

The reason for this rich cocktail is an interesting piece of evolutionary biology that would embarrass any creationist with the courage to learn about it. It is the result of repeated arms races between the snake and its prey species. Not only that, but it involves new genetic information arising, by gene duplication and mutations - contrary to creationist dogma that such a thing is impossible.

As one prey species starts to evolve resistance there is selection pressure on the snake to change its venom to overcome the resistance or loose one source of food, but, there must be a balance between retaining one food species but loosing several others if the changed venom is less effective against them. Resistance usually arises when there is a change in receptor sites on cell surfaces, on which the venom acts so the active venom molecule doesn't bind to it.

Tell me all about venomous snake and how their cocktail of venoms evolved, especially the spitting cobra venom. Venomous snakes have evolved a fascinating array of toxins and delivery mechanisms over millions of years, primarily as adaptations for defense, predation, and competition. The evolution of venom in snakes is a complex process driven by natural selection and genetic variation. Here's an overview:

1. Evolution of Venom:
   
   • Venom in snakes likely evolved from oral secretions used for predigestion in their common ancestors. Over time, these secretions became more toxic and specialized for subduing prey or deterring predators.
   • Venomous snakes possess specialized glands that produce venom, which is a complex mixture of proteins, enzymes, peptides, and other molecules.
   • The composition of venom can vary significantly among different species, even within the same genus, reflecting adaptations to their ecological niche and prey preferences.
2. Types of Venoms:
   
   • Hemotoxic venoms target the blood and tissues of prey, causing damage to blood vessels, organs, and tissues. These venoms are often found in vipers and some elapids.
   • Neurotoxic venoms affect the nervous system, causing paralysis and respiratory failure. They are common in elapids such as cobras, mambas, and coral snakes.
   • Cytotoxic venoms cause tissue damage and necrosis at the site of the bite. They are typical in some vipers and elapids.
   • Some venoms may have a combination of these effects or additional components targeting specific physiological functions.
3. Spitting Cobra Venom:
   
   • Spitting cobras (genus Naja) are renowned for their ability to project venom accurately over a considerable distance, typically aiming for the eyes of potential threats.
   • The venom of spitting cobras is primarily neurotoxic but may also contain cytotoxic components.
   • The adaptation to spit venom likely evolved as a defensive mechanism to deter predators and threats without engaging in direct physical contact.
   • The exact mechanism of venom spitting involves specialized muscles around the venom glands and modifications of the fangs and venom delivery system.
   • Spitting cobras have precise control over the muscles responsible for directing the venom, allowing them to accurately aim for the eyes of threats.
4. Evolutionary Significance:
   
   • The evolution of venom in snakes has been a significant driver of their ecological success, enabling them to efficiently capture prey and defend against predators.
   • Venom variation among snake species reflects the diverse ecological niches they occupy and their evolutionary histories.
   • Understanding the evolution and diversity of snake venoms provides insights into snake ecology, behavior, and their interactions with other organisms.

Overall, the evolution of venom in snakes, including the specialized venom of spitting cobras, is a remarkable example of adaptation and natural selection in action, shaped by millions of years of evolutionary history.

But the genes that control snake venom production are frequently duplicated, so the new gene can mutate randomly until a new shape again fits the receptors in the prey species.

Meanwhile the original, duplicated genes still produces the venom against the other prey species. So, over millions of years and probably for venoms against now extinct species, all venomous snakes will have evolved a complex mixture of different venoms and are able to prey on multiple different species.

It would be a remarkable achievement for Micheal J Behe to have persuaded creationists that anything in this process could be regarded as 'devolutionary' and the result of genes becoming less effective at what they do because of 'genetic entropy', if creationists weren't so ignorant of basic biology and so eager to have their prejudices given spurious confirmation by a 'real scientist'. As it is, they will happily cite that nonsense as an argument against evolution and pretend to have greater understanding of biology than professional biologists, oblivious of how foolish it makes them look.

As an example of intelligent design, though, if you believe in such a thing, the evidence of malevolence and stupidity in these sorts of arms races is hard to better. Not only does the same designer design snakes to kill vertebrates with venom, it then redesigns the vertebrates to become resistant to the venom, then it changes the venom to overcome the resistance it just designed, and it repeats this process over and over until the snakes need to manufacture lots of slightly different toxins just to catch their victims.

And it's all a far cry from the Biblical nonsense about 'serpents' being condemned to eat dust. (Gen 3:14)

A case in point is that of the spitting cobra which has an especially potent cocktail of toxins and can not only inject it through hollow fangs, but can control the direction and distance it can project venom, often into the eyes a the potential threat where if causes excruciating pain and near instant blindness, because the venom actually begins the digestive process by killing the tissues it contacts and causing the cells to breakdown, so the victim is left both poisoned and disabled as the skin, muscle and bone at the site of a bite become necrotic, needing radical surgery or even amputation of a limb to prevent the spread of the necrosis and opportunist bacteria that quickly colonise the wound.

But now, a team of researchers led by Professor Nicholas R Casewell who is now at Lancaster University, with former colleagues at the Centre for Snakebite Research & Interventions, Department of Tropical Disease Biology, Liverpool School of Tropical Medicine, Liverpool, UK and others, have discovered that the repurposed small molecule drug, varespladib, will block the actions of one of the two major dermonecrosis-causing toxins in spitting cobra venom, and prevent skin and muscle damage.

Apparently, a small molecule is needed because, in another example of incompetent design, the natural antibodies produced in horses and sheep, which are usually used to treat snake bites are too large to reach the envenomated tissues!
Their research is published, open access, in the journal PNAS and is explained in a Lancaster University new release:

Scientists have discovered a groundbreaking new snakebite treatment to prevent the devastating tissue damage caused by African spitting cobra venom.

Spitting cobra venom is incredibly potent and causes dermonecrosis, which presents as rapid destruction of skin, muscle and bone around the site of the snakebite, and can lead to permanent injuries and disfigurements, including limb loss and amputations in extreme cases.

Professor Nicholas Casewell and Liverpool School of Tropical Medicine colleagues including Dr Steven Hall - who is now at Lancaster University- discovered that using the repurposed small molecule drug varespladib to block one of the two major dermonecrosis-causing toxins in spitting cobra venom prevents skin and muscle damage.

Each year, it is estimated that snakebite causes long term detrimental effects in around 400,000 people across the world, with a substantial proportion of those in Africa the result of spitting cobra bites.

Currently, there is no effective treatment for tackling severe local envenoming caused by spitting cobra venom. Existing antivenoms only work on bites by other snake species and are often ineffective for treating local envenoming because antivenom antibodies are too large to effectively penetrate into the region around the bite site.

Our findings hold much promise to improve the treatment of tropical snakebite. Current treatments for spitting cobra bites are widely regarded as being ineffective, meaning that rates of disability and amputation have remained high across much of Africa. Our data shows that blocking just one of the main toxin families in spitting cobra venom will likely prevent the debilitating tissue damage seen in thousands of snakebite patients each year.

Professor Nicholas Casewell, corresponding author
Centre for Snakebite Research & Interventions
Department of Tropical Disease Biology
Liverpool School of Tropical Medicine, Liverpool, UK.

Professor Casewell’s team, led by PhD student Keirah Bartlett and Dr Steven Hall, then of LSTM and now at Lancaster University, and also involving researchers from Canada, Denmark, Costa Rica and the USA, first analysed spitting cobra venom to identify the toxins responsible for causing venom-induced dermonecrosis. The results showed that cytotoxic three-finger toxins (CTx) are largely responsible but that phospholipases A2 (PLA₂) toxins play a critical role in the process.

Local injection of the PLA₂-inhibiting drug varespladib reduced the extent of dermonecrosis, even when delivered up to an hour after the venom, and the protection conferred by the drug also extended to venom-induced muscle toxicity.

According to the authors, the findings suggest that varespladib could become an invaluable treatment against the tissue-damaging effects of black-necked and red spitting cobra venoms, which cause extensive morbidity in snakebite victims across the African continent.

Snakebite is a devastating neglected tropical disease, with tissue destruction caused by necrotic snake venoms permanently injuring hundreds of thousands of victims every year. Our work shows that the repurposed drug, Varespladib, is incredibly effective at inhibiting such necrosis caused by African spitting cobras; an exciting finding as their venoms are particularly fast-acting and destructive. We hope this work helps pave the way to future snakebite therapies that can save the lives and limbs of victims worldwide.

Dr Steven R. Hall, co-lead author
Centre for Snakebite Research & Interventions
Department of Tropical Disease Biology
Liverpool School of Tropical Medicine, Liverpool, UK.

These findings are extremely promising, not only does this offer up a new mode of treatment where previously nothing effective existed, but because varespladib has already gone through testing in human clinical trials, including for snakebite, it could be available for use in real world patients very soon.

Keirah E. Bartlett, co-lead author
Centre for Snakebite Research & Interventions
Department of Tropical Disease Biology
Liverpool School of Tropical Medicine, Liverpool, UK.

Professor Casewell’s team are already looking for viable treatments that effectively block the venom CTx. Having treatments available against both toxins has the potential to enhance the potency of varespladib, and could significantly reduce the long-term morbidity associated with spitting cobra bites in Africa and beyond.

Technical details and background are given in the team's abstract and introduction to their paper in PNAS:

Significance
Spitting cobra venoms cause extensive local tissue damage surrounding the site of a snakebite. This damage cannot be effectively prevented with current antivenom treatments, and patients are often left with life-changing wounds. In this study, we used cellular and mouse experiments to determine which toxins in certain African spitting cobra venom are responsible for causing tissue damage, revealing that a combination of two different types of toxins is required to cause pathology in vivo. We then showed that the repurposed drug, varespladib, which targets one of these toxin types, effectively prevents skin and muscle damage in mouse models of envenoming. Collectively, these findings suggest that varespladib could be an effective type of therapy for preventing snakebite morbidity in Africa.

Abstract
Snakebite envenoming is a neglected tropical disease that causes substantial mortality and morbidity globally. The venom of African spitting cobras often causes permanent injury via tissue-destructive dermonecrosis at the bite site, which is ineffectively treated by current antivenoms. To address this therapeutic gap, we identified the etiological venom toxins in Naja nigricollis venom responsible for causing local dermonecrosis. While cytotoxic three-finger toxins were primarily responsible for causing spitting cobra cytotoxicity in cultured keratinocytes, their potentiation by phospholipases A2 toxins was essential to cause dermonecrosis in vivo. This evidence of probable toxin synergism suggests that a single toxin-family inhibiting drug could prevent local envenoming. We show that local injection with the repurposed phospholipase A2-inhibiting drug varespladib significantly prevents local tissue damage caused by several spitting cobra venoms in murine models of envenoming. Our findings therefore provide a therapeutic strategy that may effectively prevent life-changing morbidity caused by snakebite in rural Africa.

Snakebite is a neglected tropical disease (NTD) that primarily affects rural communities in sub-Saharan Africa, South/South-East Asia, and Latin America and causes an estimated 138,000 deaths per annum, with a further 400,000 people maimed annually (1). Although historically receiving little attention, in 2017 the World Health Organization (WHO) added snakebite to their list of priority NTDs and subsequently devised a roadmap aiming to halve the number of deaths and disabilities attributed to snakebite by 2030 (2).

Snakebite patients affected by local tissue damage often require surgical tissue debridement or amputation to prevent the onset of life-threatening gangrene. These severe sequelae greatly reduce the quality of life of many patients (3). Severe local pathology around the bite site results from cytotoxic, myotoxic, and/or hemorrhagic venom toxins, and is most often observed after viper envenoming (1, 4). While envenoming by most elapid snakes causes neurotoxic muscle paralysis and no local tissue damage, envenoming by several cobras (Naja spp.), most notably the African spitting cobras, causes little neurotoxicity but severe, rapidly developing swelling and tissue destruction that often leads to necrosis. These spitting cobra venoms also cause ophthalmia following defensive venom-spitting events (5–7). Spitting cobra bites are perhaps most frequent in sub-Sahel regions of Africa and include bites by Naja pallida in eastern Africa (8), Naja mossambica in southern Africa (9), and Naja nigricollis, which has a wide distribution throughout northern parts of sub-Saharan Africa (10). Collectively, envenomings by spitting cobras substantially contribute to the numerous cases of severe local envenoming that result in permanent, life-afflicting morbidity across the African continent (11).

The cobra venom toxins predominantly associated with causing dermonecrotic pathology are the cytotoxic three-finger toxins (3FTx), hereafter referred to as CTx, which make up 56 to 85% of the total toxin abundance in spitting cobra venoms (12). CTx are well known to disrupt cell membranes and/or induce pore formation (13–15), which leads to cell death through a series of intracellular events related to the loss of control of plasma membrane permeability and via direct interaction with organelles, such as lysosomes (13, 14). Although CTx are the most abundant toxin type found in many cobra venoms (12), it is usually only those of the spitting cobras that cause severe local tissue damage after envenoming (1), suggesting that additional toxins are likely contributing to the severity of local envenoming. The next most abundant toxin family in several cobra venoms are the phospholipases A2 (PLA₂). While the PLA₂ toxins found in elapid venoms are often neurotoxic (1), cytolytic PLA₂ also exist which can cause tissue necrosis (16, 17). For example, the spitting cobra PLA₂ nigexine is cytolytic toward multiple tumor cell lines and reduces cell viability and cell proliferation of epithelial human amnion cells (18). It has also been proposed that toxin combinations enhance venom cytotoxicity (19–21), with PLA₂ toxins seemingly potentiating the effects of CTx (21). Understanding the relative contributions of different venom toxins to the severity of local envenoming is essential for the future design of targeted therapeutics to reduce the burden of snakebite morbidity—a key objective of our research.

Current treatment for snakebite envenoming relies on intravenous antivenom therapy, which consists of polyclonal antibodies generated via venom immunization of equines or ovines (1). While these therapeutics save countless lives, they are associated with several limitations that restrict their clinical utility, including low affordability to those in greatest need (1, 22), limited efficacy against a breadth of snake species due to venom toxin variation (22), and high incidences of severe adverse reactions in the case of some antivenoms (23, 24). The need to deliver antivenom intravenously by a medical professional in a clinical environment prolongs the time from bite to treatment by an average of 5 to 9 h due to poor hospital-accessibility in the remote, rural tropical regions where most snakebites occur (22, 25, 26). Furthermore, intravenous antivenom antibodies are too large (typically ~110 or ~150 kDa) to rapidly penetrate the envenomed peripheral tissue and neutralize the etiological cytotoxins—rendering antivenom treatment largely ineffective in reversing the swelling, blistering, and necrotic outcomes of local envenoming (1, 22, 23, 27, 28). Collectively, these limitations highlight why the development of effective therapeutics is one of the core goals of the WHO’s roadmap to reduce the impact of snakebite envenoming (2).

To address these therapeutic gaps, in this study we used a combined approach of in vitro cell cytotoxicity assays and in vivo murine models to quantify and identify the toxins responsible for venom-induced dermonecrosis caused by the most medically important African spitting cobras. Our findings demonstrate that CTx are largely responsible for cytotoxic effects observed in cellular assays using human epidermal keratinocytes, but that PLA₂ toxins contribute extensively to in vivo envenoming pathology by working in conjunction with CTx to cause dermonecrosis. Using the PLA₂-inhibiting repurposed drug varespladib (LY315920) (29–31), we then demonstrate significant reductions in venom-induced dermonecrotic pathology in vivo, suggesting that the local injection of PLA₂-inhibitory molecules following envenoming is a viable therapeutic strategy to reduce lifelong morbidity caused by spitting cobra snakebites.

So, a lot for creationists to ignore there: we have arms races leading to multiple layers of complexity to overcome problems created earlier as solutions to other problems created before that... and we have evolution by gene duplication, mutation and natural selection to produce, not 'devolved' changes but beneficial, evolutionary changes for the snakes, which no stretch of the imagination could interpret as 'genetic entropy'.

And we have all this biology to explain the complexity of the venom snakes need to kill living prey because the one thing they don't live on is dust, despite a ludicrous Bible story relating why they do.

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