European researchers have used stem cells from snakes to grow mini-glands that make venom, a finding that could address the global shortage of life-saving antivenom for snakebite.
The team, led by Hans Clevers at the Hubrecht Institute in Utrecht, the Netherlands, dissected out the venom glands of nine snake species, including the Cape Coral snake and the Cape Cobra, both endemic to southern Africa.
They coaxed adult stem cells, resident in the glands and capable of becoming any cell type in that organ, to grow in a culture and become 3D organoids. These mini-glands spontaneously produced the toxins that form the deadly snake venom, with a high degree of fidelity.
“Once we grew the venom glands as organoids, we realised that they make a lot of venom,” says Clevers.
According to the World Health Organisation (WHO) around five million people are bitten by snakes every year, causing up to 138,000 deaths and 400,000 permanent disabilities, including limb amputation.
Despite the toll, treatment for snake envenomation is a vanishing dream across much of the globe. The WHO added snakebite to its priority list of neglected tropical diseases in 2017. It noted swathes of Sub-Saharan Africa lack sufficient antivenom, an issue partly due to commercial pressures on biopharmaceutical companies.
Another hurdle is the labour-intensive nature of antivenom production. Snakes are bred on farms then milked by hand for venom, which is injected into sheep and horses that mount antibodies to fight it.
The antibodies are harvested and purified to make antivenom for humans. Clevers’ mini-glands, which the team split and regrew into hundreds more organoids, could one day mean an inexhaustible supply of venom, minus the exigencies of snake-milking.
That all hinges, of course, on whether the organoid venom is sufficiently similar to the real stuff.
“Every snake has dozens of different components in their venom. These are extremely potent molecules that are designed to stop prey from running away,” says Clevers.
Some of those toxins mop up blood-clotting factors, leading to easy bleeding and sometimes fatal brain haemorrhage. Other neurotoxins paralyse the victim and, when the breathing muscles are affected, cause death by asphyxiation.
Clevers’ team tested the mini-gland’s neurotoxin on mice muscle – it blocked nerve signalling to the muscles, just as the real venom would.
But growing organoids is an emerging skill and one finding from this study suggests different species retain their own quirks. Don’t try growing snake gland organoids at 37 degrees Celsius – human body temperature – for example. Clevers found they only grow at 32 degrees C, which you might expect for a cold-blooded reptile.
If reptilian organoids become a thing, it may help more than snakebite victims. Therapeutics derived from snake venom include blood-thinning drugs and antihypertensive medications.
First author of the study Yorick Post, also from Hubrecht Institute, sums up the possibilities: “It was amazing to see that what started with our curiosity about potential snake venom gland organoids transformed into a technology with many potential applications affecting human healthcare.”
The research appears in the journal Cell.
Paul Biegler is a philosopher, physician and Adjunct Research Fellow in Bioethics at Monash University. He received the 2012 Australasian Association of Philosophy Media Prize and his book The Ethical Treatment of Depression (MIT Press 2011) won the Australian Museum Eureka Prize for Research in Ethics.
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