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Genetic view of snake venom and the evolution of snake venom

Several animals use poisons to eliminate enemies or catch prey. Snakes are also among these venomous animals: over 600 species are now known to produce toxic cocktails - including the notorious Indian cobra.

The spectacled snake (Naja naja) belongs to the poisonous snakes. (Picture: Rahul Alvares/ Allison Bruce/ Somasekar Seshagiri).
The spectacled snake (Naja naja) belongs to the poisonous snakes. (Picture: Rahul Alvares/ Allison Bruce/ Somasekar Seshagiri), genetic view of snake venom, 2020.

Can you build immunity to snake venom?

Researchers have now decoded the genetic makeup of this cobra in detail. Their results show which genes and toxins are crucial for the snake's toxicity. In the future, this could help in the development of more effective antidotes - and possibly also provide the basis for new drugs, the team reports.

In the course of their evolution, some snakes have developed a deadly weapon: they produce toxins with which they kill their victims. Actually, the reptiles are not really after humans. Nevertheless, unfortunate encounters occur time and again. For example, every year around five million people are bitten by poisonous snakes - on average 100,000 of them are killed by the animals' toxin. 

The timely administration of an antidote can be the salvation in an emergency. However, the available means are not always equally effective and sometimes have side effects. Doctors hope that detailed insights into the genome of the poisonous reptiles will change this in the future. 

"A comprehensive catalogue of toxin genes could make it possible to develop synthetic antivenins with finely tuned compositions," according to researchers led by Kushal Suryamohan from the biotechnology company Genentech in South San Francisco. "But so far, only a few snake genomes have been published."

Indian cobra scientific research

Also little was known about the genetic characteristics of the indian cobra, the spectacled cobra (Naja naja). This poisonous snake, which is widespread in India among other countries, poses an everyday threat, especially for the rural population there. It belongs to the so-called "Big Four" among the medically relevant snakes in India. 

In order to find out more about its venom, Suryamohan's team has now looked into the cobra's genome - and published a high-quality reference genome for this species for the first time. For their study, the scientists analyzed both the genes and the gene expression in 14 different tissue types. Their results suggest that the cobra's genome contains 23,248 protein-coding genes. But which of these play a role in the snake venom - a high-protein cocktail produced by special venom glands?

Snakes poison gland in the spotlight

More detailed investigations revealed that 12,346 protein-coding genes are expressed in the cobra's venom glands, including 139 toxin genes. Among other things, they contain the building instructions for some so-called three-finger toxins, which are known for their neurotoxic, cardiotoxic and anticoagulant effects. According to the researchers, 19 of these genes are exclusively active in the venom gland and are not expressed anywhere else in the snake's body. 

In their opinion, they are the key toxins of snake venom. "In addition, a number of genes are active in the gland, which are known for their modulating effect on the poisonous function. Together with the 19 toxins, they probably trigger a wide range of symptoms such as cardiovascular disorders, muscle paralysis, nausea, blurred vision and bleeding," Suryamohan's team reports. "We believe that neutralizing these core toxins with antibodies could be an effective therapeutic strategy.

Until now, antidotes have been produced by exposing horses or sheep to the toxins of poisonous snakes. The animals then produce antibodies that can be isolated and used to treat patients. The problem, however, is that different immune reactions mean that the antibodies produced in this way do not always have their full effect on patients. Because these antivenoms also consist of animal protein, the treated patients are at risk of so-called serum sickness. 

In addition, the production of such antisera is expensive and therefore access to the drugs is often lacking, especially in developing countries. Such difficulties could be solved by the insights gained now, as the scientists explain. In the future, it may be possible to produce synthetic variants of the most important poisonous components and use them to synthesize antibodies against them. In the best case, the result would eventually be an antidote that would be more targeted and better tolerated.

New approach to therapies, uses of snake venom.

But not only that: Suryamohan's team hopes that further research into the genomes of poisonous snakes will one day enable the development of an effective broad spectrum antiserum. Comparisons with the venom gland genes of the Western Rattlesnake (Crotalus viridis) have shown that the venomousness of the two species has developed differently over the course of evolution and that their venom consists of sometimes completely different components. The Spectacled Snake therefore has 15 toxin gene families that are not found in its relative.

"If the key toxins of more snake species are identified, antibodies against them could be combined to form a broad-acting antidote," said the researchers. 

At the same time, they believe that catalogues of the most important toxin components also represent a pool of potential active substances from nature's "pharmacy": It is possible that some snake venoms contain compounds that are suitable as drugs for certain diseases.

Source: Kushal Suryamohan (Genentech Inc., South San Francisco), Nature Genetics, doi: 10.1038/s41588-019-0559-8, evolution of snake venom.