Snakes alive! The potential of venom in developing life-saving drugs

An estimated 5.4 million people worldwide are bitten by snakes every year. The World Health Organisation (WHO) says that up to 2.7 million cases involve envenoming – where the venom is injected into the victim.

Every year, between 81,410 to 137,880 people die from snakebites globally. In Malaysia, official figures from the Ministry of Health (MOH) show that between 2600 to 3700 people are bitten by snakes a year, resulting in fewer than six deaths.

But the WHO-reported figures don't reflect the true impact of snake envenomation. Under-reporting of snake-bite incidence and mortality happens worldwide for several reasons, including victims never reaching primary healthcare facilities, or opting for traditional practices in favour of hospital treatment.

“As deadly and dangerous as venom is, there are many areas to be explored in terms of its values. Besides killing prey, venom holds medical benefits, so there is interest in it for drug discovery.” 

Some survivors lose their limbs or have permanent disabilities such as paralysis, bleeding disorders, irreversible kidney failure, and tissue damage. Recognising the severity of snake-bite envenoming as a public health issue, WHO officially listed it as the most-neglected tropical disease in June 2017. Through its new NTD roadmap 2030, WHO aims to reduce mortality and disability from snake-bite envenoming by 50% over the next 12 years.

Exploring the untapped potential of cytotoxins

Though life-threatening, the venom of snakes is also life-giving. The only effective treatment to prevent or reverse snake-bite envenoming is to develop treatments from the poison.

Dr Michelle Yap Khai Khun is a lecturer at Monash University Malaysia’s School of Science whose research focuses on venom toxins' pharmacology and future biotherapeutics.

“As deadly and dangerous as venom is, there are many areas to be explored in terms of its value,” she says. “Besides killing prey, venom holds medical benefits, so there is interest in it for drug discovery,” says Dr Yap.

Biotherapeutics refers to treatments produced by or involving living cells instead of drugs made from chemicals synthesised in the laboratory.

Dr Yap's research subject is the cytotoxin contained in the venom of the Equatorial spitting (or Sumatran) cobra, which WHO classifies as a Category 1 venomous snake. As such, this snake species is of the highest priority for antivenom production, Dr Yap explains. Cytotoxins are substances that result in cell damage or cell death.

“Cobra envenomation appears to be one of the most common causes of envenomation with high rates of morbidity and mortality. It’s clinically manifested with systemically neuromuscular paralysis, ventilatory failure, and local dermonecrosis [skin tissue death]. The key venom toxin associated with dermonecrosis is due to substantial levels of cytotoxin in cobra venom,” Dr Yap says.

In her research, Dr Yap hopes to better-understand cytotoxins’ drug action – how they work and are processed by the body – with the aim of using cytotoxins for other purposes. Potential applications range from treating hypertension, to anti-cancer agents.

“Research has shown that when cancer cells are exposed to cytotoxins, they die. Now that we know they can kill cancer cells, we would like to know how this molecular target – the point at which toxins come into contact with cells – could be used in drug delivery work. We want to know how we can encapsulate the toxic agent into nanoparticles, and deliver them to targeted cancer cells.”

Treating dermonecrosis

Another of Dr Yap's objectives is to find a different antidote to dermonecrosis.

“Current treatment for envenomation involves doctors administering antivenom derived from the antibodies produced by horses,” she says.

“Antivenom of this origin needs to be injected into the bloodstream for it to be effective. But in cases of dermonecrosis, the venom is on the skin's surface. Current antivenom is ineffective in removing dermonecrosis, and that's one of its drawbacks,” she explains.

Antivenom produced in animals may also trigger allergic reactions in humans, with the worst-case scenario being sepsis. In this life-threatening condition, an infection triggers a chain reaction throughout the body that can potentially lead to tissue damage, organ failure, and death.

“If we can produce non-antibody-derived antivenom, it will be more affordable, as we can upscale production and bring down the cost.”

“European researchers have started to use human antibodies in research on antivenom. Ultimately, there needs to be antivenom that can be applied on the skin to treat dermonecrosis,” she says. Currently, victims of dermonecrosis receive surgical intervention. Post-bite treatments are often neglected because of how costly they are, causing victims to suffer from physical after-effects and psychological problems.

The global shortage of cytotoxin-targeted biotherapeutics is due to a lack of knowledge in the area, she says.

“Many studies are conducted on how cytotoxins kill cancer cells, but I want to understand how they kill human skin cells. As there are so many different species of snakes, we're trying to combine the toxin sequences to reduce the discrepancy in our study to be more inclusive.” 

Widening access to antivenom

People should take snake-bite envenomation more seriously, as it's no longer a health issue that only concerns rural people in Malaysia, says Dr Yap. Cobras and kraits are commonly found in urban areas, in addition to their usual habitats of farms, swamps, fields and jungles.

Urbanisation has resulted in snakes encroaching human habitats in the cities, and more people are keeping snakes as pets. “If a snake owner got bitten by a South American species, there would be no antivenom available to treat him,” she says.

Typically, countries stock up on antivenom of local species that are endemic to the area. There are more than 140 species of land snakes found in Malaysia. According to the Ministry of Health's (MOH) Guideline to Management of Snakebites, only about 17 of these are venomous.

While there's greater access to health facilities in urban areas, antivenom is not widely available, she adds. “They're not cheap. Therefore, they can be found at selected government hospitals only.” 

A promise of cheaper treatments

Biotherapeutics hold the promise of safer and cheaper snake envenomation treatment.

“If we can produce non-antibody-derived antivenom, it will be more affordable, as we can upscale production and bring down the cost. As it involves small molecules, it would also be more efficient in drug delivery, and can be produced in a laboratory,” Dr Yap says.

Funding continues to be the greatest challenge in her ongoing research, exacerbated by the pandemic.

“People have more interest in [funding research for] COVID-19 or other non-communicable diseases now. Snake bite is often a neglected tropical disease, but I'm glad that there's growing interest in some international funders like the Wellcome Trust, the Royal Society of Tropical Medicine and Hygiene [RSTMH], and the Hamish Ogston Foundation, to support research in this area,” she says.