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PLOS BLOGS Speaking of Medicine

Catching up with the author: Gareth Whiteley on snake venom and antivenom research

Venomous snakes are widely dispersed across the globe, occupying a range of habits in both terrestrial and marine environments. A major part of venomous snakes’ predatory success is the venom proteins, which cause rapid cardiovascular or neurological immobilisation and death of their prey. For humans, being in the wrong place at the wrong time can have disastrous consequences – snakebites against humans are often an accidental reaction to a perceived threat. Exposure to venom proteins can lead to disability, death, or other serious medical complications. Each year over 94,000 people die from snakebites globally – mostly in remote, disadvantaged areas where snakebite incidence remains relatively high.

The development of effective snakebite therapies, or antivenom, relies on researchers’ understanding of the unique protein composition of different snake venoms. Currently, genetic sequencing of venom proteins and isolation of mRNA requires sacrificing the snake and removal of the venom gland. This methodological challenge limits the scope of research in this area and is undesirable for ethical and environmental reasons, where a given species of snake may be endangered or assigned protected status.

In a PLOS Neglected Tropical Diseases research article published last June, Gareth Whiteley and colleagues present a new protocol to improve the yield of high quality RNA isolated from venom collected from live snakes. They were able to capture significant isoform diversity from the RNA and demonstrated that the isoforms they identified were identical to  isoforms extracted through traditional methods from venom glands of sacrificed snakes. These improved methods allow reliable access to venom composition data from venom acquired from live snakes, empowering researchers to expand the scope of their research while obviating the need to sacrifice snakes for venom research. The hope is that this breakthrough will save lives of both snakes and people!

I recently emailed author Gareth Whitely (@DrSnakeVenom) and asked him about some of the highlights and challenges of his research, implications for future projects, and what he’s working on now.

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Dendroaspis polylepis. Image credit: Tim Vickers, Wikimedia Commons

Your paper mentions that venomous snakes occupy an important ecological niche and some may even be endangered. How does ecology shape public health approaches to envenoming prevention and eradication?

Snakebite like many other NTDs has substantial morbidity and mortality associated with it, but it poses both unique research and public health challenges. Unlike many other NTDs, it is not possible to eradicate snakebite – venomous snakes will always be around. Further, snakes share many of the environments in which humans live and work, so paths will always cross. This poses a very different challenge to public health approaches to preventing snakebite, compared to other NTDs.

Unlike the treatments for many other NTDs, snakebite treatments are labour intensive to produce, difficult to distribute (due the requirement of a cold chain), and often very expensive. Partly because of the latter, many cheaper, yet ineffective, antivenoms have flooded the market, resulting in further morbidity and mortality. Further, unlike many other NTDs, there is more than one cause – there are over 200 medically significant venomous snakes, each has distinct venom composition, each individual venom contains a range of different toxins, and these toxins often target multiple systems in the victim – thus, one treatment does not fix all.

Although it was recognised as a NTD by the World Health Organisation in 2009, it has since lost that status. The reasoning for this decision is not entirely clear, but it perhaps reflects the wider issue of the lack of recognition and understanding of snakebite as a problem, making snakebite one of the most neglected of the neglected tropical diseases.

What are some of the opportunities and challenges of conducting fieldwork and lab-based research involving live, venomous snakes?

Working with venomous snakes presents both opportunities and challenges. Snakes are fascinating creatures, and it is great to work with them on a daily basis, especially knowing that the research we are doing will go towards helping those people affected by snakebite – i.e. disproportionately the rural poor. Further, venom is a relatively untapped source of pharmacologically relevant compounds and biological tools – tools which could open further opportunities in a range of disciplines. However, the costs associated with maintaining them is prohibitive for most, as are the lack of snake handling skills, which is a pity as this limits research to only a small handful of researchers.

What scientific compromises must be made, or creative solutions to challenges did you come up with?

Although the RNA obtained from venom is good quality, without pooling multiple specimens, repeated milking of the same specimen, or amplification of the RNA – each approach has its own experimental limitations – the quantity is currently insufficient to complete much-desired next generation sequencing (NGS). However, library preparation techniques for NGS are constantly evolving, and the required starting quantity of RNA continues to reduce. Thus, when the time arises such that venom from a single extraction contains sufficient RNA for NGS, then our protocol is ready and in place to facilitate it. Until then, this PCR-based approach outlined in our paper can be employed to capture important information on the venom gland’s transcriptome. Indeed, it would also be interesting to assess whether it is possible to isolate specific types of RNA from venom. Micro RNA has already been shown to play a role in the ontogenetic venom composition shift in snakes, and it would be interesting to explore such a concept using venom extracted from a specific individual over a life time

Our study looked at snakes, but it would be interesting to know if the observations described here are universal to all snakes, and whether they could be applied to venom producing animals other than snakes, such as spiders, scorpions, frogs and fish..

What new avenues of research do you anticipate opening up as a result of your RNA research and how might these impact areas with high prevalence of snake bites?

Our convenient, non-invasive, quick and easy strategy for improving undegraded RNA yields from venom should impact upon the ability to acquire genetic information on snake toxins, thus allowing both ourselves and others to inform future snakebite therapy design. Importantly, collection of venom during fieldwork, where access to adequate storage conditions or laboratory access for sample processing are often very limited, should also be greatly aided, thus allowing for the collection of toxin data in the field – extending the lab to the field.

It is also hoped that the findings will have an impact outside of the field of snakebite therapy research, and could be employed by ecologists, zoologists, and those who mine venom for pharmacologically interesting tools and future drugs.

What are you working on now?

The group continues to investigate the biology of snake venoms, and use this information to improve the efficacy, safety and affordability of antivenom treatment of tropical snakebite victims. Primary focus is currently on the development a polyspecific, non-cold chain liquid snake antivenom with unparalleled sub-Saharan African efficacy, with several other interesting projects ongoing, such as studying whether defense dictated the evolution of venom composition in spitting cobras. I am currently developing new analytical, statistical and computation skills to crunch large datasets, as well as ways to present and disseminate this data efficiently.

Featured Image: Indian Cobra (Naja naja). Image Credit: Kamalnv, Wikimedia Commons

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