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Scientists Figured Out the Indian Cobra's Genome—at Last

In 1891, a French physician named Albert Calmette opened a research outpost in what was then Saigon (now Ho Chi Minh City, Vietnam) to develop new vaccines for rabies and smallpox. Then the Indian cobras showed up.

The invaders sank their fangs into several of Calmette’s new neighbors, injecting molecules that rotted muscles, ruptured blood vessels, and paralyzed the nerves that told their hearts to beat and lungs to breathe. Their grisly deaths prompted him to drop infectious disease and focus on snake venom. When he returned to France, he injected Indian cobra venom into rabbits in small doses and discovered that the animals produced a serum with a protective effect: the first antivenom. Calmette began producing his anti-cobra cocktail of antibodies in donkeys and horses and in 1895, for the first time, successfully treated a human snakebite victim.

Calmette’s method still dominates antivenom production today—a practically medieval process of snake milking and horse blood harvesting that is laborious, expensive, and error-prone. What scientists have needed in order to modernize this operation is the source code for a snake’s noxious protein soup, the actual genes and nearby DNA that turn them on or off.

After two years of work, an international team of scientists has now published, in Nature Genetics, an atlas of all 38 of the Indian cobra’s chromosomes, the most complete snake genome ever assembled. It contains information no one has ever been able to piece together before: the genetic recipe for the snake’s deadly venom cocktail. They’re hoping it will serve as a roadmap to bring antivenom production into the 21st century.

“It seems like something we should have figured out 20 years ago, but until now those areas of the snake genome have been total black boxes,” says Todd Castoe, an evolutionary geneticist at the University of Texas at Arlington who was not involved in the work. Initially, scientists believe, the genes that generate venoms carried out totally different functions, usually some innocuous cellular housekeeping task. But along the way they duplicated, a common DNA-copying error. And then the extra copies acquired mutations. That happened over and over, and the proteins they produced became deadly in different ways. The result of all this evolution is that the stretches of DNA that code for venom toxins are full of repetitive sequences, making them exceedingly difficult to properly assemble. Imagine trying to solve a jigsaw puzzle where the same fluffy clouds are scattered six, eight, a dozen times in the same corner of the sky. How do you know which piece goes where?

To finally fit together these elusive sections of the genome, Somasekar Seshagiri, a geneticist and president of the SciGenom Research Foundation in Bangalore, and his collaborators used a combination of older sequencing methods with new ones that read out very long stretches of DNA. They also employed a technique that detects the 3D shape of DNA to further refine their guesses about how exactly to stitch together the structurally finicky venom regions. With the full genome in hand, the researchers then analyzed which sections of it are turned on in the venom gland but not in other tissues. That allowed them to identify the code that spells death or disablement for anyone who encounters the cobra’s bite.

Indian cobra venom isn’t just one poison; it consists of more than a dozen toxins and other substances that together launch a coordinated attack on the snake’s prey (or a hapless human victim). In the Nature Genetics paper, Seshagiri’s team identified 19 genes key to producing this lethal brew. For the first time, it establishes the links between a snake’s toxins and the genes that encode them.

The achievement not only shows scientists how to use the same methods to sequence other venomous snake species, it also unlocks the door to modernizing antivenom production. “The value of genomics is that it will allow us to produce medicines that are more concretely defined,” says Seshagiri. “Antivenoms will no longer just be like some magic potion we pull out of a horse.”

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To get there, the first step is to paste the genetic sequence for each toxin into a yeast or E. coli bacterium, then place the microbes in a bioreactor where they can multiply and rapidly churn out large quantities of each component poison. (Similar cellular factories today make everything from biofuels and beauty products to fake meat and human insulin.) Seshagiri’s collaborators in the US, India, and Germany have already successfully done this for some of the cobra’s most potent proteins, which attack nerves, heart tissue, and other cells.

The next step is to see how these isolated synthetic venom proteins interact with vast libraries of human antibodies, using a technique called a phage display, which won the 2018 Nobel Prize in Chemistry. Phages are viruses that can be genetically programmed to display various molecules—in this case antibodies—on their surface. Swish them around with vats of venom protein, and see which ones bind the best: These are the antibodies that are likely to work well in an antivenom.

Last year, researchers from Denmark and Costa Rica used such a method to make experimental antidotes that saved mice from the venom of the black mamba, a deadly African snake. But Andreas Laustsen, who leads the Danish group, knows that lab successes don’t always mean better medicines in the hands of people. An antivenom company he started in 2013, called VenomAB, folded last year. He’s still working on brewing up next-generation antivenoms, but now from inside his academic lab. The issue is not so much the science as the lack of resources. Laustsen’s lab has developed several human antibodies that can broadly neutralize toxins from different species of snake venoms that could be ready for human testing within a year, he says, but not without the tens of millions of dollars required to manufacture the drugs and finance the trials.

Better drugs are sorely needed. In Seshagiri’s native India, more than 46,000 people die every year from bites of the Big Four deadly snakes: Russell’s viper, the saw-scaled viper, the common krait, and the Indian cobra. Worldwide, poor access to affordable antivenom puts the snakebite death toll near 100,000 annually, with millions more maimed or crippled.

But that’s starting to change. The staggering numbers prompted the World Health Organization to include snakebite envenoming on its list of high-priority neglected tropical diseases in 2017. Last year the WHO set an ambitious goal to cut the number of deaths and serious injuries by snakebite in half by 2030. In 2019 the Wellcome Trust, a British biomedical research funder, launched its own $100 million push to develop better antivenoms. The availability of such resources is helping a US antivenom startup called Venomyx stay on track with its own experiments despite difficulties in securing VC funding. The company plans to begin human testing of its antibodies in 2021.

Huge roadblocks still remain. But high quality genomes of venomous snakes like the Indian cobra’s should help speed the arrival of snakebite treatments that are safer, more effective, and more humane (for the snakes, horses, and humans involved) than what Calmette came up with more than a century ago.

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