Breakthrough in dealing with snakebite

The sequencing of the genome of the Indian cobra could soon lead to improvements in the techniques used for producing anti-venom

A group of 42 scientists, led by Somasekar Seshagiri, of the SciGenome Research Foundation, Bengaluru, have sequenced the genome of the Indian cobra, Naja naja. This could soon lead to improvements in the techniques used for producing anti-venom and it might lead to the creation of a broad spectrum anti-venom effective against multiple types of snake venom.  

Snakebite causes 46,000 deaths a year in India and another 55,000-odd deaths elsewhere in the world.  Perhaps another 500,000 people suffer pain, incapacitation and paralysis, and amputations. In India, the vast majority of bites are inflicted by the “big four” — the common krait, the cobra, the sawscaled viper and the Russell’s viper. However, there are over 60 different venomous species in India.  

Snake venom is a cocktail of proteins and peptides, secreted by venom glands. Venom components can be broadly classified as neurotoxic, cytotoxic, cardiotoxic or haemotoxic, and the composition varies both between, and within species. Neuro-venoms cause paralysis, cyto venoms break up cells, while cardio venoms can stop the heart. Haemo-venoms can also lead to asphyxiation, by combining with oxygen in the blood. 

Anti-venom production is a difficult, laborious and expensive process and low volume in nature. First, the snake is “milked” by persuading it to bite meat suspended over collection jars. Then the venom is collected and small, non-lethal quantities injected into a horse. The horse fights off the effects by generating antibodies. Then, the anti venom is created by processing the horse’s blood. This creates an anti-venom specific to the snake and that anti venom will also contain other antibodies specific to equine diseases. These are not only irrelevant for humans; they can trigger severe allergic reactions.
 

Broad spectrum anti-venom can be produced by combining several of these anti-venoms but it remains a hit or miss process where the venom may not work except on a very few specific snakes. This process was first used in the 1890s, and modern methods remain practically the same. One roadblock is the lack of venom in sufficient volumes to enable research.  

The new paper in Nature Genetics claims to have decoded 95 per cent of the Naja naja genome across its 38 chromosomes, with a focus on the genome of the venom glands. The team used the gene expression data from as many as 14 different cobra tissues. 

The paper says, “12,346 venom-gland-expressed genes constitute the ‘venom-ome’ and this includes 139 genes from 33 toxin families. Among the 139 toxin genes were 19 ‘venom-ome-specific toxins’ (VSTs) that showed venom-gland-specific expression, and these probably encode the minimal core venom effector proteins. “ This was an especially tricky process. The researchers had to figure out which genes were expressed only in the venom glands to narrow down the search for key genes. 

This group of 139 genes from 33 toxin families,  and the 19 genes among this group specific to the cobra, are the most important when it comes to understanding venom creation, and in the production of anti venom. If these are synthesised, they could be used to, first, produce synthetic venom in large quantities and then, to create synthetic anti venom. Such a synthetic anti venom would also not contain equine antibodies that cause allergic reactions.  

Recombinant DNA techniques that combine genetic material from several sources could help in synthesis. The genetic sequence for each of the toxins would be inserted into yeast or E.coli bacterium, to multiply and generate large quantities of isolated toxins. Then the individual toxins could be made to interact with human antibodies to see which ones are effective. Then this could be done with compounds of toxins etc.  

This process is fiddly and laborious but it should eventually result in better anti venom, and broad spectrum anti venoms once other snake genomes are mapped. It should also lead to the development of modern lab processes, which can be scaled for volume without involving horses. While this will be expensive, WHO is targeting the halving of snakebite fatalities by 2030. So the money could be available.  

The abstract also points out "the genome could serve as a reference for snake genomes, support evolutionary studies and enable venom-driven drug discovery”. The methods used to identify venom-one specific genes could be deployed in decoding genomes of other snakes. The effects of snake venom are not well understood but there are several drugs made from active ingredients in venom. These are helpful in controlling blood pressure, breaking up clots etc. So this paper marks a major advance in the battle against  “snakebite envenoming” which WHO now classifies as a neglected tropical disease.