Biting back: QRxPharma to test 20 deadliest snake venoms

In 1967, Gosford reptile expert Athol Compton suffered a shallow, grazing bite to his thumb while attempting to capture an unfamiliar, large light brown snake with a dark head in Corner Country, in far southwest Queensland.

Powerful neurotoxins in the snake's venom caused Compton to lapse into a coma within 20 minutes. Flown to Broken Hill, he was treated unsuccessfully with brown snake antivenom, before being flown on to Adelaide.

His heart stopped twice, and he spent 30 days in an iron lung to help him breathe before being discharged, none the worse for the experience, except for a chronic but minor memory deficit.

The identity of his reptilian assailant would remain a mystery for nearly 15 years. Even today, no comprehensive study has been made of the complex cocktail of proteins and enzymes in the big snake's uniquely toxic venom.

It later emerged that Compton had had the unique misfortune to be bitten by the world's deadliest snake, the coastal taipan Oxyuranus microlepidotus, in a remote location far from the nearest supply of the only antivenom that could have saved his life had the bite been more severe. Who would ever have thought that antivenom to the coastal taipan might be useful in the semi-arid Queensland outback, more than 1500km from the coast?

It was only when a CSIRO researcher captured a second specimen in the same area more than 15 years later that herpetologists were at last able to confirm that the 'inland taipan' of outback folklore was something more substantial and dangerous than the product of a mind that had spent too long in the desert sun?

Compton belatedly qualified for recognition in the Guinness Book of Records as the only person to have been bitten by the world's deadliest snake and survived.

The inland taipan heads the list of the world's 20 most toxic terrestrial snakes -- a list dominated by Australian members of the family Elapidae.

For all the international celebrity of Australia's deadly snakes, surprisingly little is known about the composition and activity of their venoms.

But the full arsenal of modern analytical technology is now being brought to bear on the biochemical weaponry of Australia's elapid snakes in a $4.6 million research project involving Queensland biotechnology company QRxPharma and the University of Queensland, to screen venoms for molecules with therapeutic potential.

The title of the Australian Research Council Linkage Discovery grant also adds another '-omics' to the lexicon of biomolecular research: 'Venomics: molecular and functional analysis of Australian snake venoms for development of human therapeutics'.

QRxPharma chairman and CEO Dr Gary Pace says the company and its research collaborators at the University of Queensland (UQ) believe the venoms of Australian terrestrial snakes contain many highly active components, whose effects have yet to be explored.

The chief investigators in the venomics project will be Prof Martin Lavin, assistant director of the Queensland Institute of Medical Research and foundation chair of surgery at UQ, and Prof John de Jersey, head of UQ's school of molecular and microbial sciences.

QRx spokesman Alex Baker said the project would systematically investigate the biological activity all the components of the venoms of Australia's top 20 deadly snakes -- a huge task, given that each venom has some 80 to 100 different components.

The study will bring together most of the disciplines of the new biology: proteomics, genomics and transcriptomics. Biochemists will use classical techniques to isolate the various molecules present in the venoms, and Baker says the ultimate aim is to develop recombinant versions of the most promising molecules for therapeutic investigation.

The researchers will be looking for proteins, enzymes and peptides with neurotoxic or haematologic activity -- the latter will include compounds with either pro- and anti-coagulant activity.

In the early 1980s, when eminent Commonwealth Serum Laboratories venom expert, the late Dr Struan Sutherland, tested the venom of the new taipan species from outback Queensland, he was astonished to discover that the venom yield from a single bite from an adult snake was potentially capable of killing 250,000 mice, or 110 adult human males.

Like its better-known coastal cousin, O. scutellatus, the inland taipan hunts only warm-blooded prey -- small mammals and birds.

In the confines of the burrows of its preferred prey, the Australian plague rat, Rattus villosissimus, the snake's stupendously toxic venom virtually bombs its rat prey, inducing almost instant paralysis to prevent it retaliating.

Could the inland taipan provide medical science with a potent new muscle-relaxant for surgery?

A bite from Western Australia's deadly dugite snake, Pseudonaja affinis, renowned for silently infiltrating sheds and farmhouses in pursuit of mice, induces haemorrhaging by interfering with the clotting mechanism in blood. Could its venom yield a clot-busting protein to rival the current gold standard, tissue plasminogen activator?

Baker says QRx is already developing two promising compounds, a pro-coagulant and a protease inhibitor, from the venom of the eastern brown snake (Pseudonaja textiles). A common denizen of suburbia and farmlands across south-eastern Australia, the eastern brown possesses the second most toxic venom of any snake -- only its short fangs and low venom yield prevent it taking a greater toll of human life.

A venomous family

Baker said the detailed data set that would come out of the venom research was likely to be of great interest to evolutionary geneticists seeking to resolve questions about evolutionary affinities of the Australian elapids, and their more distant relationships with the Asian and African species.

Many venom components are highly conserved between Australian elapid genera, and even throughout the family; others are likely to be species-specific, reflecting the unique ecology and evolutionary history of the Australian species. Baker said it was likely that the Australian elapids had developed some unique, shared venom components during their geographic isolation.

The scarcity of venom samples, and the complexity of the venoms, had hampered phylogenetic studies in the past.

The elapids are a relatively recently evolved group, found on all the major continents except Antarctica. They include Asia's cobras, kraits and coral snakes, New World coral snakes, and Africa's mambas and cobras. While Australia accounts for only about 25 of the world's species, it has the most diverse elapid fauna -- all Australian venomous snakes are elapids.

Non-Australian elapids also include some of the world's deadliest snakes, including Asia's cobra (Naja naja) and king cobra (Ophiophagus hannah), the world's largest venomous snake, and Africa's black mamba (Dendroaspis polylepis) and green mamba (D. angusticeps).

The Brisbane study could also help resolve a long-standing controversy over origins of the world's sea snakes -- some authorities consider the sea snakes, which possess some of the deadliest venoms of all snakes, to be marine cousins of the Australian elapids; others place them within the Elapidae, as a closely related sub-family.