Scientists Successfully Grow Venom-Producing Organoids From Snake Stem Cells

Fluorescence microscopy image of snake venom gland organoids. Ravian van Ineveld, © Princess Máxima Center

Scientists have successfully grown organoids from snake stem cells capable of producing venom in what may one day prove to be an effective method of creating lab-based antivenoms and developing new venom-based treatments.

Organoids are tiny, three-dimensional cultured tissues that are derived from stem cells capable of self-organizing to form “miniature organs” complete with many cell types and able to be maintained in a lab indefinitely. In recent years, researchers have shown the potential of organoids in studying disease processes and testing potential new drugs, from the development of mini-brains to human blood vessels. Now, researchers write in the journal Cell that this is the first time organoids have been created from reptilian tissue. If commercialized, the team notes that it could be a much more efficient method for gathering venom when compared to traditional methods of raising snakes and milking their glands.

"More than 100,000 people die from snake bites every year, mostly in developing countries. Yet the methods for manufacturing antivenom haven't changed since the 19th century," said senior author Hans Clevers, from the Hubrecth Institute's (KNAW) Developmental Biology and Stem Cell Research at Utrecht University in the Netherlands, in a statement. "It's clear there is a huge unmet medical need for new treatments."

Variable toxin production (green and red) in different areas of the snake venom gland. Joep Beumer, Yorick Post, Jens Puschhof, © Hubrecht Institute

It all started with a keen sense of postgraduate curiosity. PhD students who had a connection with a Cape coral snake breeder reached out for an egg hookup and tweaked conditions used for growing human organoids – the main difference being temperature. Because the body temperature of snakes is lower than humans, venom gland organoids only grew at a temperature of 32ºC instead of 37ºC. Snakes were removed from their eggs before hatching and a small piece of tissue was removed from various organs and placed inside gels along with a mammalian “growth factor cocktail”.  

Venom gland organoids grew in just one week and were quick to replicate when manipulated by researchers, resulting in hundreds in over just two months.

"It would have been difficult to isolate stem cells from these snakes because we don't know what they look like," explained Clevers. "But it turned out we didn't need to. The cells soon began dividing and forming structures."

A look under the microscope showed cells filled with dense structures that resemble venom-holding vesicles found in the venom glands of snakes. Four types of distinct cells were identified, including active neurotoxins capable of blocking nerve firing in cell systems just like those found in venom from live snakes. Changing the factors in the growth cocktail also changed the composition of the venom, granting control over the kind of would-be venom that is produced by snakes.

"Every snake has dozens of different components in their venom. These are extremely potent molecules that are designed to stop prey from running away. They affect systems as varied as the brain, neuromuscular junctions, blood coagulation, and more. Many of them have potential bioprospecting applications for new drugs,” said Clevers.

Researchers also successfully made organoids of the snake liver, pancreas, and gut. The scientists now hope to grow venom gland organoids from 50 toxic reptilians, snakes, and other venomous animals.

The traditional method of harvesting snake venom is by inserting the animal's fangs into a cloth-covered glass jar, as is seen in this image of a cobra. milanik/Shutterstock

 

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