It’s not every day that a press release for biomedical research conjures up the Barbasol can of smuggled dinosaur DNA from “Jurassic Park.” So it stood out when a preview for a study coming out in Cell, one of the world’s most prestigious journals, mentioned not only a venomous cobra — but explained that the research came about because the scientists “knew a breeder who was able to supply some fertilized eggs.”
Ask Dr. Hans Clevers, one of the world’s top stem cell experts, how his team got the snake sample for their latest project, and he’ll tell you: His graduate students knew a guy.
“They somehow laid their hands on an egg,” said Clevers, a group leader at the Hubrecht Institute for Developmental Biology and Stem Cell Research in Utrecht, the Netherlands.
The procurement allowed the researchers to grow organoids of the snake venom glands — essentially miniature 3D versions cultivated in lab dishes. And in doing so, they opened the door to potential discoveries that could help human health.
That first egg belonged to a Cape coral snake, also known as a Cape coral cobra. With the specimen in hand, Clevers and his team removed the snake from the egg before it hatched, excised tissue samples, and then grew the venom gland organoid, they reported Thursday in Cell. They did the same with eight other species.
Organoids that model the brain or lungs or other tissue can illuminate how their bigger, human versions develop — and how that development can go awry — and act as a stand-in for patients to test if a certain drug works on cells with their particular mutations. And just as cerebral organoids build interweaving networks of neurons, these snake organoids performed as their antecedent did: They produced the toxins that comprise venom.
These lab-made toxins offer two possibilities, the scientists reported. First, it’s possible some of the toxins themselves are worth prospecting as drugs.
Second, the world needs a better, more modern way to make antivenoms. Snakebites kill up to 138,000 people a year, according to the World Health Organization, which launched an initiative last year to cut the number of snakebite-related deaths and cases of disability in half over 12 years. But making antivenom still involves milking a snake, injecting a horse with the venom, and then collecting antibodies from the horse — a sort of equine inoculation established in the late 19th century.
The venom gland organoids contained three or four different cell types that together generated the array of toxins that make up venom, Clevers said. As the researchers write, “the current study … may be developed into a production platform for (modified) snake venom, allowing novel therapeutic strategies to tackle snakebite.”
Any such application in treating snakebite remains a long way away. But researchers not involved with the study said the organoids could shed some light on the biology of venom glands more fundamentally.
“The biotechnology they are describing is a potentially wonderful addition to the toolbox of toxins research generally,” Dr. Leslie Boyer, the medical director of University of Arizona’s VIPER Institute, wrote in an email.
“What will future studies reveal about the interaction of components of complex venoms?” Boyer wrote. “Can a practical harvest of toxins be generated for cost-effective use in future applications? How do cells full of deadly toxins avoid suicide?”
To build an organoid, researchers often start with the stem cells that churn out a certain type of tissue. In this case, however, Clevers and his team didn’t know how to identify the snake’s stem cells. Instead, they just used a whole segment of tissue. They nurtured the organoids as they do those from human and mouse cells — in a dish, with some growth factors — and watched as the non-stem cells died off and the stem cells proliferated, molding into the miniature venom gland.
One difference, however, between organoids from snakes and those from mammals was that the reptilian Lilliputian organs needed to be kept a few degrees chillier, Clevers said. The human organoid-preferred 37 degrees Celsius killed the snake cells.
Cold blooded, indeed.
As Clevers and his team grew their organoids from the Cape coral snake, they started reaching out to experts in other fields who could help them analyze the toxins produced and provide samples of other species.
One of the paper’s co-authors, for example, is Freek Vonk, a reptile pro whom Clevers described as the Steve Irwin of the Netherlands. Pull up his Twitter account and it’s hard to know what to take in first: the adorableness of what appears to be a baby rhino that Vonk is spooning in one photo, or the sheer enormity of the snake draped over his shoulders in his main portrait.
Now Clevers and his team hope to build a bank of samples from dozens of venomous snakes, and are considering doing the same with lizards. Perhaps by understanding the genes that generate venom’s toxins, he said, it might be possible to come up with a better way to make an antivenom.
“For a long time, we were a gut lab,” Clevers said. “But after we developed organoids for the gut, we saw it was applicable broadly. We’ve done cancer, we’ve done infectious disease, we’ve done genetic disease.”
Now they’ve done venom.