Orange-red in color and native to Tanzania, the Naja pallida – Red spitting cobra – is a powerful enemy, 1.2 meters long. When threatened, he raised his hood and hissed loudly. If this view does not deter predators, open their mouths. The muscles around the snake’s venom glands tighten, releasing jets of venom into the eyes, nose, and mouth of the threat. When the victim’s face is hurt, the cobra takes the opportunity to lunge forward and bite, sending a large amount of venom into the victim’s body.
The poison attacks the cells in the body and damages the nervous system. For most of the cobra’s usual victims – frogs, toads, birds, and other snakes – the only fate is death. A lucky human survives but is permanently disabled.
A bad deal about antivenom
Encounters with venomous snakes kill an estimated 1.4 lakh people every year, mainly in tropical regions of Africa and Asia. Although this number is alarming, the treatment for snake bites remains ancient.
Based on the work of French scientists in the late 1800s, antivenom is made today by injecting domestic animals like horses and sheep with small amounts of snake venom. This triggers the animal’s immune system, producing antibodies to neutralize the poison. The researchers extracted the antibodies from the animal’s blood and transported them in cold storage to the hospital, where they injected them into the snake bite victims.
Difficulties in production, storage, transportation, and administration aside, antivenoms are also expensive and can have severe side effects in humans; some of them can be fatal.
That could change soon. In July 2024 the study was published in the journal Translational Medical Sciences, a team of Australian, British, Canadian, and Costa Rican scientists has reported that tinzaparin, a drug commonly used to prevent blood clots, significantly reduces cell damage caused by vomiting cobra venom. The team also found the drug reduced skin damage in mice injected with the toxin.
According to a press release, the scientists have filed a patent and may begin human clinical trials soon.
According to Kartik Sunagar, associate professor at the Center for Ecological Sciences, Indian Institute of Science (IISc), Bengaluru, who studies the evolution of snake venoms and snakebite medicines, “This discovery could pave the way for real solutions. for areas suffering the highest burden from snake morbidity.
How toxins kill cells
The venom of red and black-necked cobras – the two species used by the researchers in the study – is “poorly understood,” RNV Krishna Deepak, who studies snake venom using computational methods at Azim Premji University, Bengaluru, said.
Our understanding of how this venom kills human cells is poor, leading to a lack of progress in the development of antivenoms.
To solve this problem, researchers first investigated how spitting cobra venom affects human cells. They grow a collection of human cells in the laboratory; each member of this collection has one gene deleted. (They used CRISPR-Cas9, a Nobel-winning genome-editing tool, to build this collection.) When genes are deleted, cells cannot produce certain proteins.
The researchers then treated this collection with venom from both snakes and selected cells that were still alive. Because resistance to spitting cobra venom has been attributed to the absence of a gene, the authors concluded that the gene is involved in facilitating the venom’s effect on normal human cells.
Further research showed that many of these genes are involved in the synthesis of a sugar compound called heparan sulfate, which is known to regulate the formation of blood vessels and clots in the human body.
Blood thinners for antidote
The researchers hypothesize that the toxicity of the poison depends on the biological pathway that synthesizes heparan sulfate, artificially stopping this pathway can increase the toxic effect of the poison.
One way is to introduce a molecule that resembles heparan sulfate. When the body feels an excess of these molecules, it closes the pathway responsible for the synthesis of heparan sulfate. One such molecule is tinzaparin, a drug used to treat serious blood clots.
When the team introduced tinzaparin immediately after subjecting the cells to snake venom, the cells survived. Tinzaparin was able to protect the cells even when it was introduced an hour after the cells were exposed to the toxin. Further experiments showed that tinzaparin works by blocking the interaction between the toxin and the receptor in the cell by binding to the toxin molecule.
When the researchers injected rats with the venom of one of the two cobras along with tinzaparin, they found that the skin damage caused by the venom was less when the rats were given the drug than when they were deprived of it.
‘Hide it under your nose’
Dr Deepak, a biologist at Azim Premji University, said that using the “highly efficient CRISPR approach” to “a powerful but neglected problem” may renew the global scientific community’s interest in better understanding the mechanisms underlying snake venom.
Dr. IISc Sunagar added that the study is “one of the few research studies where the molecular mechanisms of how toxins cause damage are considered to design targeted therapies.” The study’s proposed therapeutic agent itself – tinzaparin – is cheap, readily available, and already “hidden under the nose”, says Dr Deepak.
He added that he is excited to see how different research groups follow up on the study’s findings. In the meantime, he hopes the study will gain enough attention to make a case for increased funding that will allow researchers to use “advanced and precise technologies like CRISPR-Cas9 to address the molecular mechanisms behind snakebite envenoming.”
Sayantan Datta is a science journalist and faculty member at Krea University. He tweets at @queersprings.
