Snakes on a (Three-Dimensional) Plane: Venom-Producing Organoids

By Brendan Capey on February 19th, 2020

Snake Organoids. Image from Ravian Van Ineveld. © Princess Maxima Center For Pediatric Oncology

Like any good science geek, I enjoy a healthy dose of science in my pop culture – but it’s not every day that I read a research article that immediately reminds me of the modified Barbasol can used to smuggle dinosaur embryos from the film “Jurassic Park”.

So, it was quite striking when I discovered a team of scientists, led by Professor Hans Clevers, at the Hubrecht Institute in the Netherlands had published a study in Cell, working with venomous snake embryos that they had obtained as a result of the researchers knowing a breeder that could supply them with some fertilised eggs. The acquisition allowed Clevers and his team to grow organoids of snake venom glands (miniature three-dimensional versions of the gland) that produce real venom, something never before attempted with reptilian tissues!

This all sounds pretty surreptitious, but what makes this research particularly interesting is its potential to improve access and availability of reptilian antivenoms!

Annually, 5.4 million people are estimated to be bitten by snakes, with around 81,000 to 138,000 of these cases resulting in victim fatalities. Survive that and you’ll be lucky to get away unscathed, as approximately three times as many people are subject to seriously debilitating amputations and other permanent disabilities at the hands, or should I say fangs, of snakes. Your best hope of survival, if you’re unfortunate enough to have a venomous snake sink its fangs into you, is antivenom.

As you can see, snake bites are no joke, particularly if you live in rural Africa, Latin America, or Asia – areas with the highest burden.

What’s worse, the method of antivenom production is comparatively archaic compared to other medical treatments of the 21st Century, being relatively unchanged since the Victorian era. The painstaking and dangerous process involves manually milking live snakes by hand in order to obtain enough venom, injecting the venom into a horse (or other animal) over a series of weeks, and harvesting the animal’s blood in order to obtain antibodies that neutralise the venom.

Organoid Cocktails Anyone?

Over a decade ago, Hans Clevers (or Hans “clever” as I recall my developmental biology professor once jokingly refer to him as) first discovered that stem cells (cells that have the ability to develop into specialised cell types) obtained from a mouse’s gut could be used to produce organoids when the correct cocktail of proteins and hormones (known as growth factors) were applied in the lab.

Since then, the Clevers’ lab has traditionally focused on creating organoids derived from human and mouse stem cells, including gut and liver organoids. So, what prompted the researchers to pursue the outlandish idea of growing snake venom glands?

To answer that, you have to turn to the three PhD students working in Clevers’ lab. Post, Beumer, and Puschhof had become bored of growing the same mammalian organoids. They wanted to know if snake stem cells acted in the same way as they do in mammals.

Schematic for growing organoids. Image from Post et al., 2020
https://doi.org/10.1016/j.cell.2019.11.038

By dissecting the venom glands from nine different species of snakes and applying the same tried and tested growth factor cocktail as they had always used for human and mouse tissues, the research team was able to get the reptilian cells growing into little clumps of self-organised tissue.

(I highly recommend you check out the video demonstrating 3-D imaging of the snake organoids included at the bottom of the blog!)

The only difference between the reptilian cells, and those obtained from humans was that the snake cells needed to be kept a few degrees chillier, specifically 32°C. If the usual temperature of 37°C was used, the snake cells wouldn’t survive (cue the joke about being a cold-blooded killer).

Considering that snake stem cells responded so well to human and mouse growth factors, the scientists speculated that it is likely certain aspects of these stem cells originated in a shared ancestor of mammals and reptiles, hundreds of millions of years ago. Therefore, the same growth conditions might be able to generate organoids across all vertebrate species.

Perhaps “Jurassic Park” might still be on the table…

When all growth factors were eventually removed by researchers, the cells started to transform into the functional cells responsible for venom production in snake venom glands. What’s more, by looking at the genes that were expressed in the organoids, they found a near-normal spectrum of venom factors compared with real venom glands!

Variable toxin production in different regions of the snake venom gland. Image from Joep Beumer, Yorick Post, Jens Puschhof. © Hubrecht Institute

Vats of Venom

Snake venom is a complex concoction of different toxins. Until now, it was unknown if specialised, toxin-specific cells contributed to different components of the venom within the gland, or if there was a general cell type that could produce all toxins within the venom.

By measuring what genes were expressed in single cells of both their organoids and real venom glands, the researchers were able to see exactly what every cell type produces. In both cases they found that certain cell types would be specialised to produce specific toxins.

The research team also found that cells within different regions of real snake venom glands produced differing proportions of toxins (termed regional heterogeneity). By growing organoids from stem cells in these differing regions of the gland they were able to reproduce this regional heterogeneity.

But don’t think for one minute that this manufactured venom isn’t deadly! When toxins from these organoids were applied to both muscle cells and neurones of rodents, they disrupted the function of the cells in a similar way to how real venom causes paralysis. Yikes!

No Snakes, No Problem

The research team now has plans to compile a “venom bank” of frozen organoids samples derived from 50 target species of venomous reptiles.

Assembling such a venom bank of venom-producing organoids holds potential to put an end to all the horsing around associated with current antivenom production, offering an alternative method to extract snake venom that’s a lot more convenient and safer! Not to mention, it may also open up new avenues to study snake venom for novel therapeutic uses – for instance treatments for pain, high blood pressure, and cancer.

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