The venom glands of snakes are among nature’s most potent weapons. Hans Clevers can now grow them in his lab, mass-producing little disembodied blobs that secrete the same cocktail of toxins as their natural counterparts. When I asked him where the idea of doing this came from, he chuckled. “That is what I asked my Ph.D. students,” he said.
A decade ago, Clevers realized that stem cells from a mouse’s gut, when bathed in the right chemicals, could produce organoids—miniature versions of full organs. These lentil-size blobs were simplistic replicas, but they captured many of the important features of their parent organs, from their architecture to the genes they activate. Many labs have since produced organoid versions of stomachs, retinas, lungs, livers, kidneys, and even brains. But they’ve almost always started with cells from mice or humans.
Unbeknownst to Clevers, three of his students—Yorick Post, Jens Puschhof, and Joep Beumer—had been wondering if they could make organoids from other species. And if so, what would be the most surprising organ they could grow? Quickly settling on the snake-venom gland, they contacted a breeder and acquired the egg of a Cape coral snake—a cobralike species from southern Africa. They removed the embryo’s venom gland, extracted cells from it, and put these through their usual organoid-making protocols.
If they had told Clevers about their project before they started, he would have told them that it was extremely unlikely to work. The lab produces organoids with a cocktail of human proteins and growth factors, and there was no reason to think these would work on snake stem cells. And yet, they did. The only change the students made was to grow the organoids at a lower temperature than the usual 98 degrees Fahrenheit, because reptile bodies run cooler than mammalian ones. Clevers’s team can now produce lab-grown venom glands that generate the same chemical cocktail as their real counterparts. They’ve grown organoids from eight different species, all sourced as eggs from breeders or as euthanized individuals from zoos.
The resulting organoids look like white, millimeter-wide balloons. As they grow, they fill up with venom, which the team can harvest. Actual snake venom consists of dozens of proteins; many of these aren’t toxic on their own, but become so after being modified by enzymes in the gland. Organoid venom, the team discovered, is a close match to the real deal. It consists of the right proteins, which seem to have been modified in the right way. Other researchers have managed to preserve pieces of tissue from venom glands before, but these fragments have a limited shelf life. By contrast, the organoids are stable and can be grown in the billions.
There’s something a little sinister about a lab that can mass-produce snake venom, but these organoids have many beneficial uses. Snakebites, which kill between 81,000 and 138,000 people every year, have been described as “arguably the world’s biggest hidden health crisis.” In the time you have spent reading this article so far, 20 people have been bitten, 10 have been injected with venom, and two will either die or be permanently disabled. Still, research into venom has historically been underfunded, in part because it is so difficult to work with. Venom must be “milked” from living snakes, which is a dangerous and laborious process. There are also thousands of species of venomous snakes, many of which are rare and hard to collect.
Such work might become unnecessary if Clevers’s team can make organoids from enough species. Researchers could then have ready supplies of glands and venom. They could more easily study how venom is produced, how it varies among species, and how that variation influences the severity of a bite and the efficacy of an antivenom. Clevers and his colleagues are now trying to build a library of venom-gland organoids from about 50 target species. “You can grow them and send them around the world, and now the whole world can do work on an interesting snake,” he said.
Antivenom, the only proven treatment for snakebites, is made by collecting venom from live snakes, injecting it into horses, and harvesting the antibodies that the animals produce—a technique that hasn’t changed for centuries. Organoids offer a more modern approach: Scientists could use the mini-glands to produce specific toxins, then screen for molecules that neutralize those toxins. “Although such benefits for snakebite victims may be a number of years away, the venom-gland organoids provide us with a powerful new tool to progress snakebite research towards this goal,” says Nicholas Casewell of the Liverpool School of Tropical Medicine, who worked with Clevers on this project.
This research comes in the midst of a global antivenom crisis. Pharmaceutical companies have left the market, production is half what it should be, costs are rising, and lax regulatory standards mean that many of the products are ineffective or unsafe. Venom-gland organoids could address at least some of these factors by allowing manufacturers to make antivenoms without needing to milk live snakes. “It will be interesting to see how the cost of producing venom using this system compares to the cost of purchasing venom milked from live snakes,” says Anita Malhotra of Bangor University, “since cost of antivenom is a key impediment to its wider use in countries where snakebite is a huge issue, like India and Nigeria.”
Kartik Sunagar of the Indian Institute of Science adds that even snakes that belong to the same species can produce different blends of venom in the different places they’re found. That’s a problem, since antivenom in India is made from snakes from one tiny corner of the country, and might not neutralize bites from distant regions. If researchers can make organoids from geographically distinct populations, and if that approach is more economical than setting up regional venom-collection centers, Sunagar says, “this technology can be a game-changer.”
Meanwhile, Clevers and his students have set their sights on other animals. If their organoid recipe worked for mice, humans, and snakes, “we predict that it will likely work for every vertebrate tissue,” he told me. They’re going to try to grow crocodile-tear glands, for the symbolism, but also because those glands essentially act as salt-excreting kidneys and might yield some interesting insights. At the suggestion of a Chinese colleague, they also want to grow the salivary glands of swiftlets. These birds use their saliva to bind their nests, which are collected to make bird’s nest soup—one of the most expensive edible animal products in the world. If lab-grown meat doesn’t catch on, perhaps lab-grown bird’s nest soup might.
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