Venomous snakes kill or permanently injure more than a half-million people every year. Yet researchers still know surprisingly little about the biology behind venom, complicating efforts to develop treatments. A new advance could help: Researchers have successfully grown miniature organs from snake stem cells in the lab that function just like snake venom glands; they even produce real venom.
“It’s a breakthrough,” says José María Gutiérrez, a snake venom toxicologist at the University of Costa Rica, San José, who was not involved in the study. “This work opens the possibilities for studying the cellular biology of venom-secreting cells at a very fine level, which has not been possible in the past.” The advance could also help researchers study the venom of rare snakes that are difficult to keep in captivity, he says, paving the way for new treatments for a variety of venoms.
Researchers have been creating miniorgans—or organoids—from adult human and mouse stem cells for years. These so-called pluripotent cells are able to divide and grow into new types of tissues throughout the body; scientists have coaxed them into tiny livers, guts, and even rudimentary brains. But scientists hadn’t tried the technique with reptile cells before.
“Nobody knew anything about stem cells in snakes,” says Hans Clevers, a molecular biologist at the Hubrecht Institute and one of the world’s leading organoid scientists. “We didn’t know if it was possible at all.” To find out, Clevers and colleagues removed stem cells from the venom glands of nine snake species—including the cape coral cobra and the western diamondback rattlesnake—and placed them in a cocktail of hormones and proteins called growth factors.
To the team’s surprise, the snake stem cells responded to the same growth factors that work on human and mouse cells. This suggests certain aspects of these stem cells originated hundreds of millions of years ago in a shared ancestor of mammals and reptiles.
By the end of 1 week submerged in the cocktail, the snake cells had grown into little clumps of tissue, a half-millimeter across and visible to the human eye. When the scientists removed the growth factors, the cells began to morph into the epithelial cells that produce venom in the glands of snakes. The miniorgans expressed similar genes as those in real venom glands, the team reports today in Cell.
The snake organoids even produced venom; a chemical and genetic analysis of the secretions revealed that they match the venom made by the real snakes. The labmade venom is dangerous as well: It disrupted the function of mouse muscle cells and rat neurons in a similar way to real venom.
Scientists didn’t know whether the many toxins found in snake venom are made by one general type of cell or specialized, toxin-specific cells. By sequencing RNA in individual cells and examining gene expression, Clevers’s team determined that both real venom glands and organoids contain different cell types that specialize in producing certain toxins. Organoids grown using stem cells from separate regions of the venom gland also produce toxins in different proportions, indicating that location within the organ matters.
The proportions and types of toxins in venom differ among—and even within—species. “That can be problematic for antivenom production,” says study author Yorick Post, a molecular biologist at the Hubrecht Institute. Most antivenoms are developed using one type of venom, so they only work against one type of snakebite.
Now that Clevers and his colleagues created a way to study the complexity of venom and venom glands without handling live, dangerous snakes, they plan to compile a “biobank” of frozen organoids from venomous reptiles around the world that could help researchers find broader treatments. “This would make it much easier to create antibodies,” Clevers says. The biobank could also be a “rich resource for identifying new drugs,” he adds. (Scientists think snake venom may hold the key for treatments against pain, high blood pressure, and cancer, for instance.)
Another new study, published earlier this month in Nature, could also help. Researchers have assembled a near-complete genome for the Indian cobra that could aid drug development. The organoids created by Clevers’s team will provide an “unprecedented” and “incredibly important” new avenue to complement genomic information for venomous snakes, says the senior author of the cobra study, molecular biologist Somasekar Seshagiri of the SciGenom Research Foundation. “They’ve done an amazing job making this work.”
*Correction, 23 January, 1:35 p.m.: An earlier version of this story misspelled Somasekar Seshagiri's name.