Poison sausages and platy­pus venom

looks at the weird his­tory of poi­sons turned medicines

Fortean Times - - Forum -

When re­searchers de­velop new medicines, eye of newt, adder’s fork and blind­worm’s sting don’t come close. Drugs based on ven­oms, tox­ins and poi­sonous blood sausages are med­i­cal main­stays. Now, the venom from a crea­ture that 18th cen­tury nat­u­ral­ists be­lieved was a hoax might lead to new treat­ments for a com­mon, deadly dis­ease.

We’ll be­gin in 1793 in the vil­lage of Wild­bad, south­west Ger­many, where 13 peo­ple fell ill af­ter eat­ing blood sausage. Six died. Blood sausages caused sev­eral other out­breaks of fa­tal food poi­son­ing around the same time; so be­tween 1817 and 1820 the Ger­man doc­tor and poet Justi­nus Kerner in­ves­ti­gated a ‘fat poison’ he ex­tracted from ‘sour’ sausages. De­spite killing sev­eral an­i­mals with the ex­tract, he tested the ‘fat poison’ on him­self. A few drops on the tongue caused marked dry­ing of Kerner’s mouth and throat. In 1869, John Müller, an­other Ger­man physi­cian, coined the name bot­u­lism, from

bo­tu­lus, the Latin for sausage. We now know that bo­tulinum toxin kills by ex­ces­sively re­lax­ing and paralysing mus­cles; but in tiny doses, it is in­valu­able for treat­ing, among other con­di­tions, spas­tic­ity, ex­ces­sive sweat­ing, chronic mi­graine, blad­der prob­lems and, of course, re­duc­ing the ap­pear­ance of wrin­kles. Yet just a gram of in­haled crys­talline bo­tulinum toxin would kill more than one mil­lion peo­ple.

Bo­tulinum toxin isn’t an iso­lated ex­am­ple of a poison turned medicine. In the 1970s, re­searchers dis­cov­ered that ex­tracts of the venom of the Brazil­ian pit viper ( Bothrops

jararaca) in­hib­ited an­giotensin con­vert­ing en­zyme (ACE), a

The platy­pus sank its spurs into his right arm and held on

pro­tein that helps con­trol blood pres­sure. The discovery led to the de­vel­op­ment of cap­to­pril, the first of a now widely used group of drugs called ACE in­hibitors. More re­cently, a toxin from a marine cone snail – which fires a ven­om­laden har­poon at its prey – led to zi­conotide, which of­ten al­le­vi­ates oth­er­wise in­tractable pain.

Mean­while, drugs based on ven­oms from other species help treat di­a­betes, which causes about 24,000 pre­ma­ture deaths each year in Eng­land alone. In­sulin isn’t the only hor­mone that con­trols blood sugar lev­els. Your gut, for ex­am­ple, pro­duces a pro­tein called glucagon-like pep­tide-1 (GLP-1) that has sev­eral anti-di­a­betes ac­tions. How­ever, GLP-1 is rapidly bro­ken down: about half the amount in the blood is gone in just two min­utes or so. This short ac­tion means that hu­man GLP-1 isn’t any use as a drug for di­a­betes. Then, in the early 1990s, re­searchers ex­tracted a pro­tein called ex­endin-4 from the venom of the Gila mon­ster ( Helo­derma sus­pec­tum). Ex­endin-4 trig­gers the same bi­o­log­i­cal path­ways as GLP-1. But the se­quence dif­fers. Hu­man GLP-1 is usu­ally 30 amino acids long. Amino acids are, of course, the build­ing blocks of pro­tein. Imag­ine stick­ing 30 bricks to­gether: that’s hu­man GLP-1. Now switch 15 bricks. That’s how much ex­endin-4 dif­fers: half its amino acids are dif­fer­ent from hu­man GLP-1. The dif­fer­ences make ex­endin-4 re­sis­tant to DPP-4. So, it’s bro­ken down much more slowly and the per­son with di­a­betes ben­e­fits for longer. Ex­e­natide – syn­thetic ex­endin-4 – is now a main­stay of di­a­betes treat­ment. But it’s not the only un­usual po­ten­tial source of new di­a­betes treat­ments. A re­cent study sug­gests that fu­ture drugs for di­a­betes might trace their her­itage to venom from the duck billed platy­pus ( Or­nithorhynchus anat­i­nus).

When a dried platy­pus ar­rived in Lon­don in 1799, the em­i­nent nat­u­ral­ist Ge­orge Shaw won­dered if it was a “colo­nial prank”. Af­ter all, Asian taxi­der­mists reg­u­larly stitched the head and trunk of a mon­key to a fish tail to cre­ate a ‘mer­maid’. There are, how­ever, three fam­i­lies of liv­ing monotremes; the lon­gand short-beaked echid­nas and the platy­pus. In com­mon with rep­tiles, am­phib­ians and birds, but un­like most mam­mals, the al­i­men­tary and re­pro­duc­tive tracts share an exit – thus the name monotreme, from the Greek for one hole. Monotremes also lay eggs, which pass through the same open­ing as urine and fæces. The male platy­pus has a sharp spur in the an­kle of its hind legs con­nected to a venom gland be­hind the knee. Some fos­sil mam­mals from the Me­so­zoic (252 to 66 mil­lion years ago) have sim­i­lar struc­tures. Such char­ac­ter­is­tics led some au­thors to de­scribe monotremes as prim­i­tive. Yet they are re­mark­able sur­vivors and masters of their en­vi­ron­men­tal niches. Af­ter all, an an­ces­tor of to­day’s monotremes lived in Ar­gentina, just af­ter the demise of the di­nosaurs, and they are still around – as some peo­ple, and dogs, found to their cost.

In 1816, the Ir­ish sur­geon John Jami­son shot a platy­pus in New South Wales. When the over­seer picked the in­jured an­i­mal up, the platy­pus sank its spurs into his right hand and held on un­til it was killed. The over­seer’s arm swelled “prodi­giously” and he ex­hib­ited symp­toms sim­i­lar to those of a bite from a ven­omous snake. By mas­sag­ing the an­i­mal’s hind legs, Jami­son found the platy­pus ejected poison from the spur. In 1869, a platy­pus spiked a fish­er­man in the fin­ger. The pain was in­tense, the man’s en­tire arm swelled and he de­vel­oped symp­toms rem­i­nis­cent of snakebite. Al­though painful, platy­pus venom doesn’t seem to be fa­tal to hu­mans. How­ever, sev­eral dogs died af­ter be­ing spiked. Nev­er­the­less, the ama­teur nat­u­ral­ist Au­gus­tus Sim­son, who ex­pe­ri­enced ex­cru­ci­at­ing pain af­ter be­ing spiked, re­ported that some indige­nous peo­ple would rather hold a snake than a platy­pus.

Re­cently, re­searchers from the Univer­sity of Ade­laide’s School of Bi­o­log­i­cal Sciences dis­cov­ered that monotremes ex­press GLP-1 in their in­testines and ven­oms. Platy­pus GLP-1 dif­fers in about a third of the amino acids from hu­mans, in­clud­ing the site at which DPP-4 cleaves the hor­mone. Again, it’s re­sis­tant to the rapid degra­da­tion nor­mally seen in hu­mans. In the platy­pus gut, GLP-1 reg­u­lates blood glu­cose. But it’s also in their venom, used to fight off other males in the mat­ing sea­son. This prob­a­bly trig­gered the evo­lu­tion of a sta­ble form of GLP-1. Th­ese find­ings could lead to a new di­a­betes drug. Yet we’re just scratch­ing the sur­face of venom’s phar­ma­co­log­i­cal po­ten­tial. Af­ter all, venom from a sin­gle species can con­tain hun­dreds or even sev­eral thou­sands of chem­i­cals. And bi­ol­o­gists have stud­ied few ven­omous an­i­mals in de­tail. I’m wait­ing for the first drug based on the venom of the Mon­go­lian death worm…

2 MARK GREENER is a med­i­cal writer, FT con­trib­u­tor and clin­i­cal ed­i­tor of Pharmacy Mag­a­zine.

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