Research in a venomous paradise Widely known as the most venomous continent

Most venomous Cnidarian (Box jellyfish) Most venomous Mollusc (Cone snail) Most venomous Reptile (Taipan) Most venomous Osteichthyes (Stone fish) Most venomous Arthropod (Spider – Funnel Web) Most venomous Mammal (Platypus) Most venomous Echinoderm (Sea urchin – not endemic) Why does this make us the “Lucky Country”?

• Benefits of venoms are vast and largely untapped • How and why of my favourite three! – What is the animal? – Why is it venomous? – What does the venom do? – How much of a problem is it?

Reasons to have venoms

• Venoms evolved for prey capture primarily • Prey capture venoms interfere with important physiological activities and are rarely pure substances • Defensive venoms will predominantly cause pain, but pain with no follow through can be ignored • Metabolically complex, arms race • Multi pronged attack

LD50’s?

Toxin Type LD50 (ug/kg)

Box jellyfish (Chironex fleckeri) 0.025

Batrachotoxin (Poison Dart frog) 2

Taipoxin (Inland Taipan) 2

Tetrodotoxin (Puffer fish) 9

Saxitoxin (shellfish) 9

Scorpion toxin 17

Notexin (Tiger snake) 25

Cobra Neurotoxin 75

Sodium Cyanide 10,000 Venomous Animals

• Primarily proteins or peptides • a) Neurotoxins • b) Myotoxins • c) Necrotoxins • d) Haemotoxins • e) Cardiotoxins Potential for medical uses not new

Captopril • Compounds from Pit Vipers of Brazil: Decrease high blood pressure, treating congestive heart failure. Drug approved in 1982 Aggrastat (tirofiban) • African saw-scaled viper – Central Asia: Inhibits platelet aggregation, prevents clots from growing. Drug approved in 1998 Prialt w-conotoxin MVIIA • Magical Cone: 1000 times more potent than morphine Cancer pain. Drug approved 2004

Stonefish

• Defensive venom • Extreme pain • Oedema • Hypotension • Respiratory distress • Rare occasions – death • Potential for envenomation?

Stonefish

• Stonustoxin SNTX molecules appear to bind and assemble on target membranes to form membrane-penetrating pores • Cell lysis could explain physiological effects, including edema, increased vascular permeability, and muscle damage SNTX prepore model between SNTX subunits.

Transmission EM of SNTX pores

Crystal structure of the SNTX heterodimer with SNTX-α and SNTX-β (50 nm.)

Stonefish

• Interactions not uncommon • Especially overseas • Effective antivenom Snails

• If shaped like a cone… leave it alone! – Pain – Impaired speech, vision, hearing – Nausea – Generalised pruritis – Respiratory paralysis – Cerebral oedema – Cardiac failure – Disseminated intravascular coagulopathy

Cone Snails Cone snails • Found around coral reefs and tropical marine habitats • 30 different species on a single reef • Their venoms are extremely complex—venom from an individual may have 50–200 distinct, biologically active components. • In the whole genus, many tens of thousands of distinct pharmacologically active peptides have been evolved. • Massive potential for drug development

Stingers - Box jellyfish Basic biology of box jellyfish Basic biology of box jellyfish

Large box Jellyfish

-Multiple tentacles on each 4 corners of bell -Stinging cells on tentacles only -Primarily coastal predictably seasonal -e.g. Chironex fleckeri Large box Jellyfish

– Massive local welts – Intense and immediate pain – 1.5 – 3metres of tentacle to cause death – Death in under 3 minutes – Stinger nets present to avoid jelly/bather contact – Distinct summer season – 70 deaths in Australia

Irukandji box jellyfish

-Usually single tentacle per corner of the bell -Stinging cells on bell and tentacles -Primarily offshore animals -All year around -e.g. Carukia barnesi Irukandji box jellyfish –Sting site may not be apparent –Relatively little immediate pain –Syndrome onset in 20-40mins –ANY amount of contact with stinging cells can result in onset of Irukandji syndrome –Pain (back, limb, trunk, head, overall) –Nausea, Vomiting –Hypertension –Tachycardia –Pulmonary and cerebral oedema –2 confirmed deaths –16 different species responsible Irukandji box jellyfish

Sting symptoms Nausea Vomiting 16% 10% Troponin 2% Diaphoresis 8%

Headache 3%

S.O.B 3%

Pain 58%

North Wales

Japan

Key West Red Sea Puerto Rico Hawaii Caribbean Bonaire Thailand Philippines Malaysia New Guinea Indonesia Solomon Is Timor Tarawa Torres Strait Darwin Weipa Madagascar Broome Cairns Whitsunday Fiji Gladstone Sydney

Victoria

Global reports of Irukandji Syndrome Historical Sting Data > 50 Years Historical Sting Data > 50 Years Current Sting Data < 10 Years (Carrette & Seymour, 2013)

Historical Sting Data > 50 Years Current Sting Data < 10 Years

July Aug. Sep. Oct. Nov. Dec. Jan. Feb. March April May June (Carrette & Seymour, 2013)

Historical Sting Data > 50 Years Current Sting Data < 10 Years

July Aug. Sep. Oct. Nov. Dec. Jan. Feb. March April May June • Pain is the overwhelming and predominant feature of the syndrome • Can be difficult to diagnose • May only exhibit 2 symptoms • With increased definition more cases would be highlighted • Current definition would miss the majority of cases presenting especially if clinician is not familiar with syndrome

How much of a problem?

• 200-300 stings in QLD per year • Direct cost of $2-$5 million through hospitals • Indirect cost to tourism thought to be massive (Estimated to be in excess of $500 million in 2001/2) • Only 2 confirmed deaths

Dicing with death?

• Deaths from mosquitos 725,000 • Dog attacks 25,000 per year • Icicles kill 100 people per year in Russia alone • Falling out of bed kills 450 people annually in the U.S • More than 7000 people die annually due to the doctor's bad handwriting

Where do we go from here?

• Multiple new species awaiting from spiders to jellyfish • Ridiculous untapped potential for drug and therapy discoveries