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Bacteria Are Brewing Up the Next Generation of Antivenoms

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Daniel Dempsey was a grad student stationed in the jungles of Monteverde, Costa Rica when he first encountered the danger of a snakebite. The biologist was walking through the forest one day, catching bats to study them for malaria, when he almost stepped on the black, arrow-shaped head of an enormous pit viper—a fer-de-lance. That night as he described his encounter to the local family he was staying with, they began to tear up. They told him that earlier that year a “terciopelo,” what Costa Ricans call their country’s deadliest snake, had bitten the family’s five year-old niece. The hospital, a few hours drive away, didn’t have any antivenom in their stocks. She didn’t make it.

It was Dempsey’s memory of that little girl that made him leave his job as an antibody researcher at cancer pharmaceutical company, Celgene, to focus full-time on antivenoms. Every year, at least a hundred thousand people die from a run-in with one of the 375 venomous species of snake. And right now there’s a global shortage of the only thing that can save a bite victim: antivenom. For close to 100 years, antivenom production has been a laborious process of snake-milking and horse blood harvesting. But now, with synthetic biology and next-generation sequencing techniques, scientists are pushing the field into the future. Along with education and smart distribution, those advances could help end this global public health crisis.

A number of new biotech startups, both in the US and Europe, are signing on to tackle the antivenom problem. Dempsey’s, called Venomyx, is using vats of antibody-burping bacteria to engineer their cure. In a communal basement lab in San Francisco’s Tenderloin neighborhood, Dempsey and his employees Deepankar Roy and Alex Capovilla share bench, fridge, and instrument space to develop their pipeline of four antivenoms.

The first thing you might notice about the lab, if you know anything about antivenom production, is the distinct absence of farm animals. For decades, scientists have injected horses, or sometimes sheep, with a diluted version of snake venom, then collected their blood after a period of incubation and immune system triggering. Manufacturers use chemicals like ammonium sulfate or molecular separation methods to purify the antibodies. Then they suspend them in liquid and voila: antivenom. But to create their antibodies, Dempsey’s team is trading the equine incubator for the workhorse of the synthetic biology world: E. Coli, which they genetically modified to produce the venom-fighting stuff.

First, they injected a llama with sub-lethal amounts of snake venom. After sequencing the DNA of her antibody-creating B cells, they built a library of all the molecules those genes encoded. Then they exposed the library to tons of toxins found in snake venom—and after seeing which toxins stuck, they picked the tightest-binding molecules, and stuck their genes inside E. coli. The bacteria, when put in a bioreactor with the right mix of media and other molecules, kick out a soup of antibodies, which will go into different antivenoms for Asia, Africa, North America, and South America. Dempsey says that because llama antibodies are roughly 80 percent similar to the ones humans make, they don’t set off damaging immune responses, which can happen with horse and sheep-derived products.

But camelids aren’t the only new idea in town. A different startup, Copenhagen-based VenomAB, is instead using “humanized” antibodies to build out its antivenom product pipeline, which it has been developing with a Swedish pharmaceutical manufacturer. That process, which is popular in the cancer treatment world, involves designing human-like antibodies with variable regions that can bind different toxins, and getting bacteria to belch them out, just like they do for human insulin and other recombinant drug therapies. Both companies say that avoiding herds of hundreds or thousands of large mammals will bring down the time it takes to make the serums, as well as the cost. Typical doses can cost between $800 and $1,000 in rural Africa, and up to $14,000 in the US.

Solving the antivenom shortage, of course, is more complicated than simply developing more efficient production lines. The vast majority of mortalities fall on poor, isolated communities like subsistence farmers in Sub-Saharan Africa and Southeast Asia, so big manufacturers in the US and Europe have been slow to get into the game. In that vacuum, companies in Asia and India have flooded the market with subpar products, that might not even be applicable to places like Africa that have totally different species of snakes. The other big problem is that the antivenoms currently on the market all require refrigeration. Developing countries, with their spotty infrastructure, needs shelf-stable serums that can survive tropical temperatures. “Good antivenoms can be made really affordably—$14 or $20 a vial,” says Leslie Boyer, founding director of the University of Arizona’s VIPER Institute. “But it’s the distribution costs that make the situation untenable.”

These new approaches to antivenom development are valuable from a research standpoint. But they may not be necessary to solve the global shortage. “Do we need the most cutting edge technologies modern science can offer?” says Boyer. “No. What we need is better distribution networks, and certification programs to regulate the quality of the products and education programs to build trust with communities.” To that end, she and her colleagues in Arizona are teaming up with experts from Mexico and Africa to launch an international awareness campaign to areas hardest hit by snakebites.

Dempsey is hoping that in a few years from now, when his shelf-stable, horse-free antivenoms are ready for prime time, the efforts of people like Boyer will make it easier to get treatments to people where they need it most. Places like the jungles of the Congo and the mountains of Costa Rica.

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