Synthetic biology tackles global anti-venom shortage

When the medical charity Doctors Without Borders called the worldwide shortage of snake anti-venom a public health crisis last September, Brazilian biochemist Paulo Lee Ho wasn’t surprised. He has spent his career at Sao Paulo’s Butantan Institute searching for better ways to create anti-venom to treat bites from coral snakes.

Conventional methods rely on natural coral-snake venom, which is hard to come by: The snakes produce only small amounts with each bite and are hard to raise in captivity. So, Paulo and others have turned to proteomics and synthetic biology in the hope of improving the quality and availability of anti-venom. These efforts are now bearing fruit.

Last month, Paulo and his colleagues reported that they had engineered short pieces of DNA that, when injected into mice, triggered antibodies against coral-snake venom. The scientists then boosted the animals’ immune response by injecting them with small pieces of synthetic venom antibodies synthesised in Escherichia coli bacteria. In a separate study, also published last month, another group of researchers in Brazil used synthetic antibody fragments to neutralise the effects of bites by the pit viper Bothrops jararacussu. Such progress is encouraging, given the severe medical burden caused by snakebites in the developing world, says Robert Harrison, head of the Alistair Reid Venom Research Unit at the Liverpool School of Tropical Medicine, UK.

Each year, around 90,000 people die after being bitten by venomous snakes. Yet, anti-venoms are still made using a method that has not changed for more than a century. Large animals, typically horses, are injected with small amounts of purified proteins extracted from snake venom, which prompts the production of antibodies. Plasma containing these antibodies is then given to snakebite victims. But this lifesaving treatment is limited in important ways. Each anti-venom is effective against only a single species or, at most, a small group. And the drugs must be refrigerated, a major problem in tropical countries without reliable electricity. “When you think about it, it’s amazing these anti-venoms work at all,” says Leslie Boyer, director of theVenom,Immunochemistry, Pharmacology and Emergency Response Institute at the University of Arizona in Tucson.

Trial and error
The number of pharmaceutical companies that make anti-venoms is declining, because the drugs are not very profitable. In 2010, for instance, pharmaceutical giant Sanofi of Paris, ended production of the anti-venom Fav-Afrique, which is designed to treat the bites of 10 of Africa’s most poisonous snakes. Paulo hopes that his approach will help fill this void. Rather than relying on venom milked from live coral snakes, he began with small pieces of coral-snake DNA that code for venom toxins.

He and his colleagues injected these DNA pieces into mice to prime their immune systems; a month later, they gave the animals a booster shot containing synthetic venom antibodies. Only 60% of mice injected with a lethal dose of coral-snake venom survived after receiving Paulo’s experimental treatment, compared to nearly 100% for existing anti-venoms. But Paulo is undaunted. “This result shows there are other ways to obtain neutralising antibodies,” he says. “May be to get better results, we need to try again but use more antibodies. We just don’t know yet.”

The second Brazilian team, led by molecular biologist Carla Fernandes of the Fundaco Oswaldo Cruz (Fiocruz) biomedical research institute in Porto Velho, tested a different technique, using a phage display library to make synthetic versions of the antibodies that llamas produced when they were injected with Bothrops jararacussu snake venom. Giving these antibodies to snakebite victims would eliminate the need to use animal plasma. It also could reduce muscle damage and tissue death at the site of the bite, compared to traditional anti-venoms, because the synthetic antibodies are smaller and better able to penetrate into the tissue. The path to newer anti-venoms isn’t straight, but researchers believe that moving quickly is key. To Leslie, however, the anti-venom shortage is not caused by a lack of science. “It costs 14 bucks to make a vial of anti-venom that is $14,000 in the US,” she says. “The expensive parts aren’t the science — it’s everyone wanting a cut of the profits that drives the price up.”