Superlative

The truck was stuck.

Not just a little stuck. I’ve been a little stuck before and I know what that looks like. The truck was a lot stuck. It was so-deep-in-the-mud-that-I-can’t-see-one-of-the-back-wheels stuck. It was we-aren’t-going-anywhere-soon stuck.

On either side of the roadside, the savannah grass was nearly a foot over the top of the roof rack, and so thick that I couldn’t see more than a foot into it.

And that’s when something dawned on me.

It had been just a week since a German architect had disappeared. It had happened just a few miles from where I was standing, blankly staring at the spinning tires and flying mud near the border of Ethiopia and South Sudan.

His truck had gotten stuck, too. And he wandered away for help. And then he was gone. Lions, it was presumed. Or maybe a leopard. There aren’t many big cats left in this part of the world, but they’re there. And often hungry.¹

A scout with a gun was awaiting us at a local ranger station. But we hadn’t gotten to the ranger station yet. We didn’t have a gun. We didn’t have anything.

“How ironic would it be,” I asked the interpreter with whom I was working, a Will-Smith-as-the-Fresh-Prince doppelgänger who called himself Rico Jinka, “if I got eaten by a lion while writing a book about the world’s deadliest animals?”

“Ironic?” Rico asked.

“Funny,” I said.

Rico stared into the grass for a moment, swallowed hard, and scrunched up his sweat-covered face.

“That wouldn’t be funny,” he said. “If you get eaten, we all get eaten.”

Our party of four—Rico and me, plus his friends Eramis and Berechet—redeployed in and around the truck. Eramis and I pushed and pulled. Rico threw rocks under the wheels. Berechet put the gas pedal on the floor and worked the wheel back and forth. The mud smelled like death. The truck lurched forward and I fell backward in front of the left fender. The truck missed me by an inch or maybe two, bathing me in foul water and slimy mud as it passed.

I only later realized the real irony. I was worried about lions. But the creatures far more likely to kill me weren’t lurking in the grass. They were the tiny organisms lying in wait in the mud. And they were the much larger organisms working alongside me to extricate the truck.

In a good year—that is to say a good year for them, not us—lions kill 100 humans worldwide.

Mosquitoes kill 725,000 people a year, mostly via malaria, which runs rampant in that part of Africa. Other tiny creatures such as tsetse flies, roundworms, and the parasite Trypanosoma cruzi, which is carried by the aptly named assassin bug, kill tens of thousands more.

But humans are even deadlier, and that’s just to other humans. Nearly 500,000 people are intentionally killed by other people each year. Another 1.33 million die in motor vehicle accidents²—like getting run over while trying to get a truck out of the mud.

I was freaked out about the wrong things.

But “deadliest,” of course, is subjective in all sorts of ways.

Population size matters. There are about 20,000 lions remaining in Africa—and quadrillions of malaria-causing mosquitoes. When it comes to deaths per individual killer, lions are deadlier.

Size matters, too. Mosquitoes are a lot smaller than lions. When it comes to deaths per pound of killer, the insects rule the day.

How fast does someone or something die after being attacked? How many deadly attacks can one creature accomplish in a day, or over its lifetime? How toxic is its poison or venom?

And then there’s the question of “deadly to whom?” Most animals, after all, aren’t nearly as deadly to humans as they are to the animals they normally prey upon.

No matter how you measure, though, one thing is clear: The animals we often worry about—“movie scary” creatures like spiders, snakes, and sharks—aren’t anywhere close to as dangerous to us as we have been led to fear.

There isn’t a household in the United States where you won’t find a spider—there’s almost certainly one watching you right now—but spider bites account for just seven American deaths per year, on average.³ You are four times more likely to be killed by lightning.⁴

I’ve never ceased to leap away when I cross paths with a snake on a hike, and my skin crawls for hours afterward, but in the United States my odds of being killed by any kind of reptile this year are about 1 in 50 million. I’m about 5,000 times more likely to be killed in a car crash, but I don’t get the heebie-jeebies every time I get into my Mazda.⁵

Australia spends millions of dollars each year erecting and maintaining shark nets to protect popular beaches, using a “national interest exemption” to get around environmental laws that otherwise would ban the nets, which regularly trap and kill whales, sea turtles, and seals.⁶ That’s despite the fact that sharks account for just one death per year in a nation of 24 million people.

Far less important than what we should truly be scared of, though, is what we can learn from organisms that have proven, in one way or another, to be prolific killers.

And there are a lot of killer organisms out there.

HOW THE WORLD’S DEADLIEST POISONS ARE LEADING US TO CANCER CURES

The square-shaped acrylic containers were each about the size of a tissue box. There were three of them on the table before me and inside each one, submerged in embalming fluid, was the decapitated head of a lamb.

And if that’s not gross enough, these weren’t just any lambs. These were cyclopean lambs, with a central eye socket and a fleshy tube projecting from their foreheads. I leaned down to stare into the vacant eye of the one closest to me and released an involuntary shudder.

“That’s . . . so . . . cool,” I told my host at the US Department of Agriculture’s Poisonous Plant Research Laboratory, research plant physiologist Dan Cook.

What I really meant by “cool” was “creepy,” but I didn’t want to dissuade Cook from showing me any of the other things he kept hidden away in his lab, where scientists work to advise agriculturalists worldwide on the deadly things growing all around them.

Cook didn’t disappoint. Soon we were standing inside what might be the world’s most dangerous herbarium, a room full of metal cabinets, each one stuffed to the brim with folders holding dried stems, leaves, berries, and flowers of poisonous plants from around the world.

I briefly thought of my favorite character from the Harry Potter chronicles, “herbologist” Neville Longbottom. “Oh my God,” I thought, “what Neville could do with a room like this.”

What muggles can do with a room like this is pretty amazing, too.

When an animal is poisoned, but a farmer or rancher doesn’t know how it happened, they can send a sample from the afflicted creature’s stomach to the lab. The lab connects the sample to the chemical signatures of the plants in these files, then sends photos of the offending plant back to the farmer or rancher so they know what to watch out for and remove from their land. “There aren’t many labs like this left in the world,” Cook said, “so we get asked for help from people all over.”

Among the frequently pulled files are those for plants that seem to have come straight out of a Hogwarts spell, like black chokecherry, Prunus virginiana melanocarpa; grassy deathcamas, Zigadenus gramineus; and greasewood, Sarcobatus vermiculatus.

And then there’s the folder marked “Veratrum californicum,” inside of which are samples of the plant’s broad, oval leaves and Star of David–shaped flowers. When pregnant sheep eat V. californicum, they get a dose of a steroidal alkaloid known as 11-deoxojervine, which scientists also call “cyclopamine” for the effects it has on the lambs of poisoned ewes.

We’ve known since the 1960s what cyclopamine does to sheep, but decades passed before we knew why: The chemical inhibits a signaling pathway that tells embryonic cells how to go from a little zygote to a big complex organism. The result? Really messed-up sheep that don’t usually survive long after birth, if they make it that far at all.

Cyclopamine is one of the most dangerous plants in the world to sheep. But Cook and his colleague, rangeland management expert Jim Pfister, told me it’s not a universally dangerous chemical.

“When we’re talking about toxicity in plants, there are a lot of variables,” Pfister said. “How much of it is available? When is it available? What time of the year is it toxic? There are plants in which toxicity decreases during some times of the year and increases in others. And then, of course, it depends on what animal ingests it. What’s poisonous to one isn’t poisonous to all.”

Plants can be acutely poisonous, meaning humans and animals that come into contact with them get sick or die immediately. This includes plants like water hemlock, Cicuta douglasii, which the lab has declared to be “the most violently toxic plant that grows in North America.” Just a small amount of the toxin it carries, cicutoxin, can move into the central nervous system in seconds and can cause violent convulsions, grand mal seizures, and death.⁷

Plants can also be chronically poisonous, meaning that they’ll only cause harm if ingested over a long period of time. That’s what happens with locoweed, a name given to certain species of the Astragalus and Oxytropis genera. The moniker means what you think: Animals that eat locoweed exhibit signs—like blank staring, extreme nervousness, self-imposed isolation, and violence—that make them seem crazy.

Plants can also be harmless to the animal that eats them, but deadly to that animal’s kin. That’s the case with the needles of the Ponderosa pine, Pinus ponderosa, which at a height of up to 270 feet also happens to be one of the tallest trees in the world. Cattle often graze on the needles when other forage is lacking due to snow, or incidentally eat it when grazing near a tree. And that’s generally fine for the cows, even pregnant ones, but bad for the calves pregnant cows carry—the diterpene acids in the needles are an abortifacient.

Similarly, plant poisons can be transmitted from mother to offspring via milk. That’s the situation with Madagascar ragwort, Senecio madagascariensis, which carries toxic alkaloids that can accumulate in the livers of animals like horses and cause hepatic disease in a foal, even if the mother was unaffected by the poison.⁸

It’s the job of lab scientists like Cook and Pfister to work out the permutations for as many poisonous plants as they possibly can. And while their primary mission is agricultural, the “spinoff benefits” of such research are pharmaceutical.⁹

Take, for instance, cyclopamine. The gene that causes embryonic chaos in sheep also plays a vital role in the development of several forms of cancer in humans. Researchers from Johns Hopkins realized in the mid-1990s that if cyclopamine could interrupt that gene in sheep, it might also be able to stop the development of those cancers in humans.¹⁰ Scientists have had a hard time synthesizing the chemical since that time, though, and V. californicum, which grows best in high-elevation meadows and streams, has proven a challenge to grow on farms.¹¹ That’s why the drug company PellePharm recently contracted with the US Forest Service to harvest the roots of the plant in the Manti-La Sal National Forest, which, as it happens, is just about 70 miles north of the gigantic aspen forest Pando. PellePharm is using the cyclopamine it harvests to produce a test treatment for Gorlin syndrome, a highly malignant basal cell cancer. What started with mutant sheep may end with hope for tens of thousands of people around the world.

It took more than a half a century from the discovery of V. californicum’s toxic properties to reach the point that it was being exploited for pharmaceutical use. These days, though, scientists are increasingly looking to poisonous plants for secrets to combating a wide range of human diseases.

“It’s likely that every poisonous plant in the world has secondary compounds, in small amounts, that could be very beneficial to human health,” Pfister said.

That’s true of true hemlock, Conium maculatum, which was used to put prisoners to death in ancient Greece. It’s been used in traditional medicine for sufferers of breast cancer, although, like many traditional remedies, that treatment was widely ignored by modern scientists. That finally changed in 2014, when a research team from the University of Kalyani in India showed an ethanolic hemlock extract also had the ability to induce apoptosis through the regulation of p53—the same gene that elephants use to kill off cells that have mutated in malignant ways.¹² The plant used to execute Socrates may wind up saving a lot of other people’s lives.

Another killer that could become a lifesaver is deadly nightshade, Atropa belladonna, which some scientists believe would have been in the potion that brought death “like an untimely frost / Upon the sweetest flower of all the field” in Shakespeare’s Romeo and Juliet. It’s been used for centuries by assassins, and its alluringly plump and shiny purple berries are occasionally to blame for the deaths of children. But one of its many chemical compounds, atropine, has been used for nearly as long as an anesthetic. Atropine is still in demand across the world today as the standard antidote for nerve gas poisoning, a tragically frequent occurrence even though nerve agents have been illegal under international law for decades.¹³

The deadly castor bean, Ricinus communis, is the source of the poison ricin, exposure to which can cause vomiting, diarrhea, seizures, and death.¹⁴ Ricin has been used in a number of modern terrorist attacks and political assassinations, but is also a superstar “phytoremediator” recently proven to be exceptionally effective at extracting from contaminated soil toxic metals like cadmium, lead, and actinium,¹⁵ and chemical contaminants like hexachlorocyclohexane and DDT.¹⁶

While well-known for their deadly qualities—and increasingly for their pharmaceutical and industrial upsides—hemlock, nightshade, and castor beans are not the most dangerous plants in the world. Not when it comes to human body count, at least. In fact, they’re not even close.

But similar to those three poisons, the photosynthetic eukaryote that holds that deadly distinction may also have tremendous potential for helping humanity. If, that is, we can tap into it.

HOW A DEADLY REPUTATION HAMSTRINGS ONE OF THE WORLD’S MOST PHARMACEUTICALLY PROMISING PLANTS

When Khalid El Sayed published his first study on the cancer-killing potential of compounds known as cembranoids in 1998, he knew it was unlikely the discovery would be saving lives any time soon. The soft coral in which the molecule was found, Sinularia gardineri, grew in the Red Sea. And although it showed promise against lung, skin, and colon cancer in human cells, and leukemia in mice,¹⁷ “it’s just not easy to farm things that only grow in the ocean,” he told me.

El Sayed knew, however, that cembranoids—which have a chemical structure based on a 14-carbon ring—were quite widespread in nature. “So if we could find them somewhere else where they are easier to cultivate,” he said, “it could be very helpful.”

What El Sayed discovered in the years that followed was surprising and ripe with potential. Yet the chemistry professor from the University of Louisiana at Monroe is still having a hard time getting funding for further research.

That’s because the cembranoid source El Sayed now believes has the greatest potential for fighting cancer also causes 7 million deaths worldwide each year, mostly by way of lung disease and lung cancer. That’s right: Tobacco could be a vital weapon in the fight against cancer.¹⁸

Let’s let that hang there for a moment or two while we build some context: When I ask folks what plant kills more people than any other, their minds rarely go straight to tobacco. Nicotiana tabacum by itself, after all, isn’t acutely dangerous. If you were to chew up and swallow a leaf you’d probably have one heck of a stomachache, but you’re not likely to fall over and die.

But tobacco leaves are some of the most chemically loaded foliage in the world. Even before it’s processed and loaded up with additional ingredients, there are at least 3,000 chemicals in tobacco,¹⁹ and El Sayed believes the number might be closer to 5,000. Most notorious among these chemicals is nicotine, an oily liquid that acts as a stimulant when absorbed into the body’s bloodstream, where it wreaks havoc on the autonomic nervous system and skeletal muscle cells, and causes one of the hardest-to-break addictions in the world.

Cigarette companies knew this for decades before they admitted it to the public, and went through extraordinary lengths to conceal the true dangers of using their products.²⁰ While reasonable people can disagree about how obvious it should have been that inhaling smoke of any sort wasn’t a great health choice, it’s worth noting that as the dangers of smoking became more well-known in the latter half of the twentieth century, cigarette company executives took the craven step of intentionally manipulating their products to make them more addictive. And while Big Tobacco was ordered by a federal court to admit to that conspiracy in 2006, the companies fought doing so for another eleven years.²¹

During that same period, US tobacco company profit margins went up more than 75 percent,²² mostly because every time the government increases the taxes on cigarettes, the companies tack on a few more pennies, too.²³ Those profits haven’t carried over to tobacco farmers, though: Market consolidation has hammered producers in North Carolina and Virginia, where the vast majority of US tobacco is grown. Nationwide, crop values fell from $1.83 billion in 2014 to $1.27 billion in 2016.

“Ultimately tobacco is a very sustainable crop,” El Sayed said, noting that Native Americans were cultivating the plant long before the arrival of Christopher Columbus, and that it was first commercially cultivated in Europe in the 1550s.²⁴ “It’s a prosperous crop, agriculturally very valuable, and many states already depend on it economically.”

With recent research showing tobacco cembranoids have potential for inhibiting the growth of new blood vessels in breast and prostate tumors,²⁵ El Sayed figured the time was ripe for further investment in research related to beneficial uses for the plant—which could, he said, potentially save jobs and lives at the same time.

Now, if you’re looking for a grant aimed at preventing smoking and tobacco use, you might be in luck: The Centers for Disease Control and Prevention, the National Center for Chronic Disease Prevention and Health Promotion, and the Office on Smoking and Health are among the US government agencies literally giving money away for science-based prevention. But if you’re trying to demonstrate beneficial uses for tobacco, El Sayed said, “it’s very difficult to get funding.”

El Sayed said the tobacco lobby is almost certainly interested in his research, which also suggests that if cembranoids were left in the tobacco put into cigarettes—right now those compounds are scrubbed out, ostensibly to improve taste—it could make cigarettes less cancerous. “But there are several funding agencies that will not fund you if you have had any sort of tobacco funding,” he said.

The National Institutes of Health, for instance, will look to see if researchers who are applying for grants have previously had tobacco industry funding. Many top-tier research institutes, like Johns Hopkins and the Mayo Clinic, outright prohibit their scientists from accepting cigarette industry support. And some top journals, including those in the British Medical Journal line of publications, won’t even consider a submission connected to tobacco money.²⁶

“I certainly understand,” El Sayed said with a sigh, “but I’m not promoting tobacco smoking. We do know that some people are going to smoke it anyway, though, and we might be able to minimize the harm. And then, of course, it would be very good to make better use of tobacco to begin with as a pharmaceutical or a supplement.”

As University of Manchester epidemiologist Anne Charlton pointed out in a letter for the Journal of the Royal Society of Medicine in 2004, the global success of cigarettes in the nineteenth and twentieth centuries essentially hijacked a plant that had, upon its initial introduction in Europe, “acquired a reputation as a panacea, to the extent of being called the ‘holy herb’ and ‘God’s remedy.’”

“I suggest we should set aside the prejudices generated by the ill-effects of tobacco smoking,” Charlton concluded, “and examine the leaves systematically for substances of therapeutic value.”

Researchers at Australia’s La Trobe University have done just that, focusing their work not only on the leaves but the rest of the plant as well. In doing so, they have discovered a molecule called NaD1, found in the trumpet-shaped pink and white flowers of an ornamental species of tobacco, that can be used to conduct a precision strike on cancer cells while leaving the healthy surrounding cells unscathed.²⁷ That’s caused Susan Lawler, the head of La Trobe’s Department of Environmental Management and Ecology, to begin thinking wistfully about the future in ways similar to El Sayed. “Imagine fields of tobacco grown for their flowers instead of their leaves,” she wrote for The Conversation, “leading to an outburst of health-conscious tobacco farming.”²⁸

Imagine indeed. For when we only see things as dangerous, the biggest danger is we might miss their true potential.

WHY THE WORLD’S MOST POISONOUS FROGS DON’T POISON THEMSELVES

The frog was a father, carrying its tadpoles on its back. And as I slowly approached it to get a closer look, I was taken by the way in which something could be so nurturing and so deadly at the same time.

“They’re good papas,” said my guide, Diego Gustavo Ahuanari Arujo, a member of the Cocama ethnic group who was showing me around the forests where he grew up near Colombia’s Amacayacu National Park. “Once the eggs are hatched, they carry the babies to keep them safe.”

I lifted my camera and got closer.

The frog was only inches from my lens when Arujo spoke up. “It is more likely to jump away from you than toward you,” he said, “but maybe you should not take the chance?”

I snapped one more frame and then took a step away.

“OK,” I said, “so now can I pick it up?”

“Sure,” Arujo said, “if you want to be dead in the next five minutes.”

“But how will we lick it then?”

Arujo was clearly tired of my kidding. “Fine,” he said. “You lick the poison frog. But give me your phone so I can take a video of you dying. We will make lots of money on YouTube and my village will be rich.”

We found several dart frogs that day, and more that night when we searched the forest by flashlight. “One of the first things people teach their children here is to stay away from those frogs,” Arujo told me. “You have to teach them, because children love frogs.”

Some adults do, too. Evolutionary biologist Rebecca Tarvin has spent a lot of time in the Colombian forests collecting and studying—and yes, even licking—some poisonous frogs. The “mild” frogs Tarvin tried tasted like sushi. “I could tell on my tongue the area that had touched the frog,” she once told NPR, “and the feeling kept spreading until my mouth was kind of numb.”²⁹

Tarvin’s tongues-on approach to science might not be for everyone, but much of her research is deadly serious. Just a milligram of poison from some of the species she doesn’t lick, like the golden poison dart frog, is strong enough to kill ten adult humans. As such, the dart frog known as Phyllobates terribilis is often considered to be the most poisonous animal in the world.

So how is it dart frogs don’t poison themselves? At least for some dart frogs, Tarvin has learned, the secret appears to be a single amino acid in the protein typically impacted by the deadly toxin epibatidine. A slight change in the shape of that receptor makes it impossible for epibatidine to attach itself to the protein. Essentially, the toxin just slides right off.

But there’s a problem with that strategy: That same receptor is needed for the frogs’ brains to work properly. So epibatidine-carrying dart frogs have evolved to have other amino acid changes—kind of like biological detours—that allow the protein to still do its job. Lots of species of dart frogs have evolved in this way, but the workaround shows up differently in different lineages—as when different highway engineers choose different ways to build a bypass.³⁰

It’s only because of these chemical workarounds that these frogs can even exist. But their existence alone doesn’t ensure we can keep studying the hundreds of toxins they create; where they’re doing that existing matters, too. That’s because frogs are bioprospectors. They make their toxins by picking up novel compounds from the things they eat in the wild, which make those compounds from the things they eat, and so on. In captivity, dart frogs lose their toxicity. We can’t re-create an entire rainforest ecosystem in a lab, so we can’t study these toxins unless wild frogs stay wild.

Which, of course, means protecting the rainforests. And we’ve been really bad at that. Pollution and habitat loss have resulted in a world in which about a quarter of the dart frog species we know about are endangered—and there are likely many more that will leave this planet before we even identify them. When herpetologist Shirley Jennifer Serrano Rojas published her discovery of an orange-striped black poison dart frog called Ameerega shihuemoy in 2017, she lamented that without a conservation plan, the creature might be gone before it could really be studied.³¹

Amphibians have survived several global mass extinctions. But because they rely on clean water and damp habitats, and often live in areas like rainforests that are overly exploited for human needs, they’ve been particularly hard hit by the Holocene Extinction.³² Making matters more perilous: It appears poisonous amphibians are naturally more likely to face extinction than their nontoxic kin in the first place, perhaps by as much as 60 percent.³³ It’s not yet clear why this is, but researchers have hypothesized it could be because producing toxins is energetically costly, or that animals with chemical defenses become “strong” enough to move into habitats that are more marginally conducive to sustaining life—and thus become more vulnerable in the long term.³⁴

Natural toxins, of course, have proven to be exceptionally good roadmaps for pharmaceuticals—and the deadlier the toxin, the better the potential. With each dart frog we lose, we’re shutting down another of the world’s best pharmacies.

That’s why researchers are racing to synthesize as many dart frog toxins as possible. To that end, scientists scored a big win in 2016 when they discovered a twenty-four-step process for creating another deadly dart frog poison, batrachotoxin,³⁵ which interferes with bioelectric signaling, and may thus be a good research tool for understanding how nerves conduct electricity.

But it can take a very long time to synthesize a single toxin. The publication of a recipe for synthetic batrachotoxin came forty-seven years after the poison was first identified in the wild.³⁶

One toxin down, thousands to go.

And that’s just the ones we get from frogs.

HOW DEADLY SNAKES MADE HUMANS POSSIBLE

I know better than to be afraid of snakes.

Only a quarter of all snakes are venomous. Only a small fraction of venomous snakes carry a potent enough toxin, and enough of it, to kill a human. An even smaller number of those potential killers live in areas humans frequent. Many of those are shy and skittish, only attacking if provoked and, even then, often with venomless strikes known as “dry bites.” And in most of the places where I spend my time, antivenom treatments for the most likely biters are readily available in local hospitals, albeit often abusively expensive.³⁷ All told, death by snakebite is an extremely rare tragedy in the United States. Not counting the zealots who use rattlesnakes in religious ceremonies,³⁸ the delusionals who refuse to seek medical treatment when bitten,³⁹ the blunderers who try to pick up rattlers they encounter in the wild,⁴⁰ and the occasional distraught individual who commits suicide by cobra (and yes, that’s a real thing⁴¹), the number of people killed by snakes in the United States is often two or fewer each year—despite the fact venomous snakes exist in all forty-eight contiguous states and account for as many as 8,000 bites a year.

I know all of this. But when a traveling reptile zoo called Creature Encounters brought a yellow-and-white Burmese python—a completely venom-less snake named Narcissa—to a party my then-six-year-old daughter was attending, I encouraged her to go pet it, and then prayed to every god I could remember that she wouldn’t ask me to hold her hand while she did so.

I’m embarrassed by this. It’s irrational. But it turns out I’m in good company—or at least a lot of company. Ophidiophobia is one of the most common fears in the world, and it might be the most common animal phobia.⁴²

There’s a long-running nature-versus-nurture debate as to why so many people are so afraid of snakes, with research that appears to back both schools of thought. In 2011 researchers from Rutgers, Carnegie Mellon, and the University of Virginia published a study showing that, while humans appear to be hard-wired to recognize slithering animals more quickly than other animals, we have to learn to be afraid of snakes, either from a bad experience or, more commonly, from the reactions of people around us.⁴³ In 2017, though, researchers from the Max Planck Institutes in Germany and Uppsala University in Sweden came to a seemingly different conclusion. They studied the pupils of nearly fifty 6-month-old infants and saw rapid dilation—a common reaction to fear—when the babies, who presumably had no experience with snakes yet, were shown photos of various serpents, indicating fright could be innate.⁴⁴

Whether my fear of snakes is something I learned, something I carry in the trenches of my DNA, or a combination of both, anthropologist Lynne Isbell—the same scientist who observed that giraffes often bend down to eat, rather than stretching for the leaves on the tallest branches of trees—believes snakes are responsible for making me who I am, and her who she is, and you who you are. Her Snake Detection Theory suggests primates wouldn’t have evolved as we have were it not for the need to be alert to snakes—and the strongly selective evolutionary pressures of not being good at doing so.

Snakes, after all, are some of the world’s most effective killers. In parts of the developing world where some of the most poisonous snakes live, including India, Indonesia, Nigeria, Pakistan, and Bangladesh, they still claim a lot of human lives. The World Health Organization estimates that more than 80,000 people die each year as a result of venomous snake bites, and that many more suffer injuries resulting in amputations and other permanent disabilities.⁴⁵ Not including other Homo sapiens, snakes kill more humans than any other vertebrate—and they can do it fast. In some cases, snake venom can be fatal in just minutes.

Over tens of thousands of years, Isbell believes, the threat posed to humans by snakes may have contributed to the creation of distinctively human behaviors, including the act of pointing and perhaps even the development of language. And, in the grander scheme of survival, snakes also might have applied evolutionary pressure to the physical characteristics defining many primate species.⁴⁶ Isbell has observed, for instance, that primates from places where there are lots of venomous snakes have better vision and bigger brains than the ones existing in places where there aren’t as many of those sorts of predators. As evidence, she points to the happy-go-lucky lemurs of Madagascar who, as primates go, have small brains and poor vision.⁴⁷ The lemurs evolved, she notes, without having to worry about venomous serpents—there are eighty species of snake on that African island nation, but none of them are venomous.

There are countless other pressures at play in our evolution, though, so Isbell and her collaborators have taken a deep dive into the primate brain for neurological corroboration of the theory. And in the pulvinar, an area of the thalamus that provides fast visual-information processing, they seem to have found what they were looking for: a section of the primate brain that appears to “light up” selectively when monkeys see pictures of snakes—even though the monkeys, which happened to be Asian macaques, had been raised in captivity and had never seen a snake before. Shown other pictures, the same area of the macaques’ brains wasn’t engaged.⁴⁸

One of Isbell’s later studies showed that even a brief glimpse of the pattern of a snake—just an inch of gopher snake skin exposed between two green towels on the forest floor—was sufficient to capture the attention of wild vervet monkeys at the Mpala Research Centre on the Laikipia Plateau in central Kenya.⁴⁹ “My plan was to show the monkeys an inch of a snake’s skin, then take it out another inch, and another until they recognized it as a snake,” Isbell told me. “It didn’t occur to me they would detect it with just an inch showing. That told me that it’s not leglessness. It’s not the shape of the snake. It’s the scales. It has to be the scales.”

That finding aligned with yet another of Isbell’s studies, in which white-faced capuchin monkeys from South America were also shown to have unique responses to the sight of snake scale patterns. The capuchins showed greater antipredator behaviors when exposed to realistic-looking models of both boas and rattlesnakes than when they were presented with similar models that didn’t have a snake scale pattern.⁵⁰

These three primates, from three vastly different parts of the world, were all connected by an attentiveness to snakes that appears to come from a shared brain function specifically designed to help simians avoid serpents like the pit vipers of Asia, cobras of southeast Africa, and aspers of South America.

Do humans share this innate attentiveness? Isbell’s frequent collaborator, Jan Van Strien of Erasmus University Rotterdam in the Netherlands, believes we do. Using electrophysiological tests of human subjects, he has demonstrated that, regardless of whether we consciously feel a fear of serpents, our brains respond to images of snakes with a spike in electrical activity, called an early posterior negativity, that far exceeds the levels occurring when we see images of other animals that are creepy and crawly—and widely seen as treacherous—such as slugs, turtles, spiders, or crocodiles.⁵¹ A later study co-authored by Isbell and Van Strien showed significantly heightened early posterior negativity in response to snake skin over similarly colored lizard skin or bird plumage—which, once again, was unrelated to whether test subjects believed themselves to be afraid of snakes.⁵² Bit by bit, the evidence is getting stronger: Humans and other primates are hard-wired to become quickly alert to, if not outright fear, snakes—all part of an evolutionary arms race Isbell believes likely began with constrictors (which makes me feel a little less sheepish about my terror over Narcissa the python), but which was turbo-charged as snakes evolved to inject their prey with some of the deadliest toxins in the animal kingdom.

WHY ECONOMIC INEQUITY STALLED DEVELOPMENT OF VENOM-BASED MEDICINES

While studies are beginning to suggest that snakes played an important role in the formation of our most visceral danger reflexes, we’re only just beginning to study whether snakes and other venomous animals might have the power to impact our lives in other ways.

Writing for BioEssays in 2011, a team of biologists from Leiden University in the Netherlands called venoms “a grossly under-explored resource in pharmacological prospecting,” and blamed a disparity in knowledge about reptiles—owing in part to fundamental fear—for “the neglect of thousands of species of potential medical use.”⁵³

Seeking to address that neglect a few years later, a consortium of European Union research organizations set out to create the largest database of toxins in history. But when its four-year Venomics Project ended, its list of venoms only included about 200 of the 150,000 venomous species in the world. And that’s just the venomous ones—those that can inject toxins into their victims, usually through a bite or a sting. There are many more poisonous animals, like dart frogs, that can spread their toxins by touch alone or, in the ultimate act of revenge, kill their predators from the pit of those predators’ stomachs.

One of the main reasons we don’t invest more scientific effort into understanding venoms is the same reason we don’t spend more on research aimed at preventing and treating malaria: The people who would most benefit are poor. Venom analysis, after all, has historically been centered on creating antivenoms—and the majority of people who need antivenoms are in developing nations.

Even when antivenoms do exist, there are “chronic gaps in antivenom supply globally that have cumulatively cost millions of lives, maimed millions more, and contributed to the burden of poverty and disenfranchisement that lingers heavily over many nations,” David Williams of the Australian Venom Research Unit wrote in the British Medical Journal in 2015, responding to news that one of the world’s largest pharmaceutical companies would no longer make the antivenom Doctors Without Borders most commonly uses to treat snakebites in Africa.

But Williams also noted that the lack of this particular antivenom was just insult on top of injury. Most Africans already couldn’t access the care they needed in time to save life and limb. “Experts have been urging the relevant authorities to redress this denial of access to an essential medicine,” he wrote, “without any meaningful response.”⁵⁴

Where the world community has failed to act, Williams wrote, a new breed of snake oil salesman has swept in. In Ghana and Chad, for example, the adoption of ineffective antivenoms resulted in snakebite fatalities rising more than 500 percent in a single year. Meanwhile, indifference has stymied attempts to get even a rudimentary view of how badly needed and readily available antivenoms are. When public health researchers from the Netherlands attempted to survey antivenom manufacturers, national health authorities, and global poison centers on the issue, they received responses from less than a quarter of the organizations they sought to survey.⁵⁵ Based on the information they were able to gather, the researchers concluded that health agencies in nations heavily impacted by snakebites had engaged in few epidemiological studies, infrequent training for health workers, and paltry development of national abatement strategies. With little international support to address the antivenom shortage, they wrote, those nations had focused health efforts in areas where they could be successful—which meant leaving many snakebite victims to their fates.

The difference in snakebite outcomes between the developed and developing world is striking and shameful. It means that even though I’m afraid of snakes, I really have no reason to be, while people in less affluent areas of the world who have every reason to be afraid must accept death-by-snake as a part of life.

There has, however, been a recent surge in attentiveness to venoms. Not because the developed world has suddenly begun to care more, but rather because technological advancements have offered researchers the opportunity to evaluate venoms for purposes that impact rich nations, too.

The European Union’s Venomics project, for instance, explicitly sought to create “innovative receptor-targeted drugs as well as novel therapeutic avenues” by focusing on “inflammation, diabetes, auto-immune diseases, obesity and allergies.” And while those remedies could certainly “trickle down” to poorer nations, the participants in the project made it no secret that their primary goal was economic, not humanitarian.⁵⁶ Whatever the motive, though, the result has been the identification of hundreds of new proteins and peptides that researchers are turning into life-saving therapeutics.

Though enjoying newfound attention, applied venomics isn’t a new field of science. In 1968, a research team from pharmacologist John Vane’s lab at the Royal College of Surgeons demonstrated the venom of a Brazilian pit viper known as Bothrops jararaca could be used as an angiotensin-converting enzyme inhibitor, which causes the relaxation of blood vessels and results in lowered blood pressure. That discovery quickly led to the development of captopril, which gained FDA acceptance to be marketed in the United States in 1981 and is still used today to treat hypertension, kidney problems, and congestive heart disease.⁵⁷

Captopril was revolutionary, but it was also a lucky break. Indigenous groups in Brazil had pointed researchers in the direction of the viper, which they had long used as a source of poison for the tips of their arrows.⁵⁸

“The medicines of today are based upon thousands of years of knowledge,” Vane noted in his acceptance speech for the Nobel Prize in medicine in 1982. Although he was being honored for his work in discovering prostaglandins, hormone-like substances that govern several important processes in the body, in his short banquet speech Vane made specific reference to the pharmaceutical promise of venom, adding “the new medicines of tomorrow will be based on the discoveries that are being made now, arising from basic research in laboratories around the world.”⁵⁹

And yet there was no rush to discover venom-based medicines in the decades that followed. The research was, at that point, just too hard. There can be thousands of toxic peptides in the venom of a single species—meaning scientists have to sort through tens of millions of chemical structures to figure out which does what. To do this, they first have to identify a venom that affects a biological process—one that drops a test mouse’s blood pressure, for instance. Then they have to break that venom down into smaller and smaller component parts, looking for the single molecule, or combination of several molecules, responsible for the effect they’ve seen.

It wasn’t until quite recently that advances in genetic sequencing and in vitro DNA reproduction made it possible for researchers to see, better and faster, the conditions in which a molecule becomes active. That allowed scientists to more easily find promising chemical candidates without the benefit of, as Vane had put it in his Nobel speech, “folklore” and “serendipity.”

These days we can sort through the chemical structures of venoms with the help of supercomputers. And we can fuse together toxins from different animals to create designer molecules.⁶⁰ These advances have led to a surge in research interest in venom, and particularly in the venom of the deadliest creatures in the world, like the killers that most often show up on lists of the world’s deadliest snakes.

Assigning a superlative designation to a snake’s deadliness is difficult, since they hunt all sorts of different prey. Even among common prey, such as mice, some snakes kill faster, others kill more frequently, some produce more venom, some produce more toxic venom, and some—by virtue of size and appetite—just kill more. Nonetheless, there are a few snakes that show up on just about every herpetologist’s you-don’t-want-to-mess-with-this-one list, including the inland taipan, the black mamba, and the saw-scaled viper.⁶¹

The inland taipan, Oxyuranus microlepidotus, was the creature that sent an Australian teenage snake-wrangling celebrity named Nathan Chetcuti into a nearly deadly coma in 2017. Often cited as the snake with the deadliest “lethal dose 50” rating—that’s the amount of venom it takes to kill half of the unfortunate test mice that are injected in a lab—the taipan’s venom contains a component capable of forming compounds that play key roles in inflammation and stopping bleeding. It may also have a chemical that can relax the muscles responsible for the contraction of blood vessel walls.⁶²

Mamba venom isn’t quite as toxic as taipan venom, but mambas are a lot bigger and a lot quicker—likely the fastest venomous snake in the world. Dendroaspis polylepis venom works fast, too; it quickly paralyzes the snake’s prey, giving the mamba time to savor its meal. That quality intrigued researchers whose analysis of mamba venom revealed the presence of a painkiller seemingly just as strong as morphine.⁶³ Set against a worldwide opioid addiction crisis created in large part by doctors seeking to address their patients’ pain, the discovery that mamba venom is such an effective inhibitor of acid-sensing ion channels—a principal pathway for pain in humans—has sparked hopes we might soon be on the verge of creating less-addictive painkillers.

In terms of a raw human body count, there is no genus of snake deadlier to humans than the saw-scaled viper, Echis carinatus, one of eight related species across Africa, the Middle East, and South Asia responsible for tens of thousands of deaths each year. It’s also helped doctors save a lot of lives, as the source of an antiplatelet drug called tirofiban, which prevents blood clotting during a heart attack and can be administered during surgery to treat coronary artery blockage.⁶⁴ Tirofiban is unlikely to be the last drug emanating from saw-scaled viper venom, though. In 2017 molecular biologists did a tandem mass spectrometry analysis of venom from E. carinatus snakes from India, learning as they did so that the viper may be something of a one-stop shop for scores of proteins also found in the venom of a variety of other snakes, plus a few novel ones that will be further examined in the years to come.⁶⁵

Terrestrial snakes are the most studied venomous creatures in the world. But even though there are only about 600 species of venomous snakes, we’re still a long way away from a full reckoning of their pharmaceutical potential.⁶⁶

We’re even further away from understanding the poisons of Poseidon.

WHY THE WORLD’S LARGEST PHARMACY MIGHT BE UNDER THE SEA

The sting wasn’t bad at first.

I was diving with my wife in Los Arcos National Marine Park in Mexico when it happened. I’d spotted a manta ray and was trying to follow it from above when I swam right through a crowd of small jellyfish.

One got me. It was like a quick jab with a needle, not even enough to get me to surface in the moment. By that evening, though, I had a welt on my back the size of a 20-peso piece. It stayed there for a long time, so red, bulbous, and ugly that I wouldn’t walk around shirtless for months. I felt sorry for myself only until I did an online search for photographs of other people’s jelly injuries; the results were a gag-inducing collection of tangled lacerations, constellations of pustules, and dark scabs. After that I just felt lucky.

Oceanic cnidarians, including jellyfish, anemones, and corals, use harpoon-like tentacles called nematocysts to envenomate their prey and fight off predators. Some cnidarian stings are just annoying. Others can be deadly. The deadliest to humans are box jellyfish, agile swimmers with twenty-four eyes and exceptionally potent toxins, which exist in oceans around the world and like to hang out near the beaches as much as humans do. By some estimates, the box jellies claim 100 human lives a year via a fast-acting envenomation that can stop an adult’s heart in minutes.⁶⁷

The box jelly’s venom holds unbridled potential. Yet as Bryan Fry, a venomologist at Australia’s University of Queensland, has noted, more scientific studies are conducted on snake venom in a single year than have ever been published about jelly venom.⁶⁸ This may be in part because jelly venom is hard to get, so Fry set out to develop a technique for making it easier.

He knew ethanol could induce nematocyst discharge in other cnidarians, so he and his collaborators gathered up some box jellies of the species Chironex fleckeri, also known as the sea wasp. They dipped the sea wasps’ tentacles in ethyl alcohol for thirty seconds, waited a day for the proteins to disperse, and then sent the liquid through a centrifuge.⁶⁹ The result was pure sea wasp venom, a handful of new proteins and peptides to study, and a process quickly adopted by researchers examining other cnidarians. Among those who have already leaned on Fry’s findings are scientists studying cold-water sea anemones, Pacific sea nettles, and the enormous lion’s mane jellyfish. An entire phylum of some 10,000 venomous animals has been unlocked.

Of course, cnidarians aren’t the only venomous creatures of the sea. Anyone who knows the tragic story of Steve Irwin can tell you that. Irwin, who rose to prominence as the brazen and buoyant “Crocodile Hunter,” had gleefully survived encounters with crocodiles and poisonous snakes; he used to joke that his worst injuries came from parrots. But it was a rather unlikely suspect, a stingray, that caused his death in 2006 while filming a documentary series that was all-too-aptly called Ocean’s Deadliest.

Stingrays are among 1,200 species of venomous fish that, until quite recently, have been just as widely ignored as cnidarians. The most toxic ones known to science so far—and the “so far” is important here, given the vast unexplored reaches of our ocean—hail from the genus Synanceia: the tropical stonefish.

Stonefish, named for their rocky camouflage, secrete neurotoxins from their sharp dorsal spikes that can induce pain, swelling, hypotension, and respiratory distress in unfortunate humans who accidentally step on one.

Although we parted ways with stonefish somewhere in the neighborhood of 500 million years ago, we’ve still got a few things in common. For instance, a protein found in Synanceia called stonustoxin appears to be an ancient relative of a human protein called perforin. In humans, perforin is used to destroy cells that have been infected or have mutated in cancerous ways, but it also causes pancreatic cell destruction in type 1 diabetes patients and transplant rejection in bone marrow recipients.

Scientists have long known that perforin works, in both its positive and negative capacities, by creating a pore on the face of a cell big enough to allow toxins to enter and kill it from the inside out. In 2015, they learned how it does that—it begins when two subunits of stonustoxin interact, forming a crystal structure that starts pore formation. Once they realized how the pores began, scientists could start looking for chemicals that might inhibit that process from the onset.⁷⁰ If that happens, it could help the nearly 30 percent of leukemia patients whose bodies reject a bone marrow transplant.

If there’s one deadly sea creature that has more pharmaceutical potential than any other,⁷¹ it’s the fearsome cone snail. Venom from members of the genus Conus is among the fastest-acting in the world, and these gastropods have come to be known as “cigarette snails” because, as the story goes, if one stung you, you’d only have enough time for a single smoke before your heart stopped.

The truth is that only a few of the hundreds of species of cone snails can deliver enough venom to threaten a human, but their toxic sting does work as fast as advertised—even faster if you happen to be a passing fish, which can go from merrily swimming to helplessly paralyzed in a fraction of a second. It’s that sort of speed that intrigues researchers like Frank Marí, a biochemist whose cone snail “farm” at the National Institute of Standards and Technology has been at the center of dozens of discoveries involving the neurotoxic peptide the snails carry, known as conotoxin.

Marí has his milking technique down pat. He entices the snails in his lab with a dead goldfish and waits for the animals to start swinging their toothed proboscis back and forth. Then, at the last moment, Marí replaces the fish with a latex-topped vial.⁷²

That’s a technique that builds on a far more hilarious process developed in the 1980s by a University of Utah undergraduate named Chris Hopkins, who inflated a condom and rubbed a goldfish on it before lowering it into a tank full of venomous snails. “The sight of an inflated condom floating at the surface with a tethered snail swinging like a pendulum below it was one of those moments that should have been recorded with a camera,” Hopkins’ adviser, neuroscientist Baldomero Olivera, later wrote.⁷³

Olivera’s lab later isolated a peptide from Conus magus, the magical cone snail, that was the basis for ziconotide, a spinal-injected pain reliever 1,000 times stronger than morphine for patients with severe chronic pain. Researchers suspect the thousands of additional peptides in cone snail venoms may one day be used for fighting tuberculosis, cancer, nicotine addiction, Alzheimer’s, Parkinson’s, schizophrenia, multiple sclerosis, and diabetes.⁷⁴

HOW KILLER SPIDERS AND FRIENDLY GOATS ARE WORKING TOGETHER TO MAKE SHOES

Bert Turnbull’s 1973 treatise on the ecology of spiders for the Annual Review of Entomology reads like the start of a horror movie trailer.

“They are found over the entire life-supporting land masses of the world,” he wrote. “Where any form of terrestrial life exists it is safe to assume there will be spiders living nearby.”⁷⁵

And wherever they are, Turnbull’s research showed, they are hungry. To support their voracious appetites, they evolved to be some of the most prolific killers in the world.

By way of comparison, humans collectively kill and eat about 400 million tons of meat and fish each year. All the whales in the ocean might eat as much as 500 tons of meat. But according to estimates based on the work Turnbull did during his long career, the global spider community kills and eats as much as 800 million tons of other animals each year.⁷⁶

For Washington Post data geek Christopher Ingraham, the fact that spiders eat the equivalent weight of 8,000 aircraft carriers in meat each year wasn’t disturbing enough, so he did a little additional math. “The total biomass of all adult humans on Earth is estimated to be 287 million tons,” he wrote, adding that even if you tacked on another 70 million tons for all the kids, “spiders could eat all of us and still be hungry.”⁷⁷

Along with snakes, spiders are some of the most feared animals in the world by humans, and yet the world would be a tremendously more frightening place if they didn’t exist. All those hundreds of millions of tons of spider food, after all, are made up of members of the orders Diptera (that’s flies), Hemiptera (cicadas, aphids, and the like), Hymenoptera (sawflies, wasps, bees, and ants), Collembola (springtails), Coleoptera (beetles), Lepidoptera (butterflies and moths), and Orthoptera (grasshoppers, locusts, and crickets).⁷⁸

Spiders also eat a tremendous number of other spiders, meaning that killing a spider simply leaves fewer predators for the other spiders. For arachnophobes, that’s one heck of a lousy zero-sum game.

Part of the reason spiders eat so much is they’ve been wildly successful as an evolutionary clade. There are nearly 45,000 known species of spider. And just about all of them are venomous. What biochemical treasures are lurking in all that venom? We have almost no clue at all. Researchers have evaluated only a few thousand of the likely 10 million different active molecules in the venom of the world’s spiders. That nascent search, though, has already yielded molecules that may be effective for treating muscular dystrophy and chronic pain.⁷⁹

If there’s one good way to get rich men to invest in research, it’s to establish a potential cure for erectile dysfunction. And that’s what scientists studying the Brazilian wandering spider, Phoneutria fera, have done. After learning that the bite of the spider, which is found in rainforests throughout South America, can cause a persistent erection, the researchers gathered up some older rats who, like many older men, were having a bit of trouble in that department, and gave the rodents a dose of one of the spider’s toxins, called PnTx2-6. Since PnTx2-6 works differently than the active molecules in the most common ED medications, it may give hope to the one-third of men who don’t respond to drugs like Viagra, Levitra, and Cialis.⁸⁰

That’s not all spiders are good for, though.

Spiders wouldn’t be nearly so deadly, after all, if not for one of their most emblematic characteristics—the webs most of them spin to catch their prey. Webs’ filaments are stronger than steel, and that sort of strength makes spider silk an incredibly enticing substance for makers of products like ropes, nets, parachutes, and bullet-resistant materials. And since spider silk is biocompatible—it won’t be rejected by the human body—the proteins that make it at once so strong and elastic are being explored as possible materials from which to make artificial ligaments, tendons, bone, and skin.

Just one problem: Owing largely to the fact that spiders are territorial and often cannibalistic, spider silk is exceptionally hard to farm. And that’s why Randy Lewis doesn’t work with spiders, but goats.

Goats, of course, don’t spin webs. But Lewis learned that by transplanting two spider genes into the goats in his lab at Utah State University, he could get the ungulates to produce milk that contains spider silk proteins. When the milk is frozen, separated, thawed, and filtered, the result is a fine white powder that, when turned into a solution and pulled through a syringe needle, turns into a fiber that is very light and very strong—just like a spider’s suspension line.⁸¹

Goats aren’t the only organisms capable of receiving a spider gene. Lewis and others have also experimented with silkworms, alfalfa, and bacteria. And spider thread from several of these sources is starting to see its way into the market; in 2016, for instance, Adidas announced it was working on a running shoe made from synthetic spider silk that won’t just be lightweight and strong, but also will biodegrade when you’re done with it, bringing new meaning to the German brand’s motto “Impossible Is Nothing.”

WHY MAKING MOSQUITOES LESS DEADLY COULD PRESENT AN EVEN BIGGER DANGER

Anyone who has watched Bill Gates’s 2009 TED Talk about fighting malaria remembers the moment the mischievous founder of Microsoft opened a glass jar filled with mosquitoes, releasing them into the auditorium and onto an unsuspecting crowd in Long Beach, California.

“Malaria is, of course, transmitted by mosquitoes,” he told the audience as he unleashed the bugs. “I brought some here, so you could experience this. We’ll let them roam around the auditorium a little bit. There’s no reason only poor people should have this experience.”⁸²

If you haven’t seen the talk, I highly recommend it. And at the point Gates starts to open the jar, just about 5 minutes and 10 seconds in, close your eyes and listen to the laughter.

Gates’s insects weren’t actually infected, and it’s clear most of the people in the crowd understood that the second he popped the lid off the jar. The audience immediately laughed and applauded. Yet Gates still hastened to tell his fans they had nothing to be afraid of. In a room full of very privileged people, the mere possibility there might be someone in the room who believed a crazed billionaire would put people’s lives at risk was too frightening to let stand for more than a few seconds.⁸³

Thanks to the efforts of people like Gates—who frequently notes the global market for hair-loss cures is greater than what we spend to stop malaria,⁸⁴ and who has spent hundreds of millions of his own dollars to rectify that shameful fact—many people now at least recognize that the animal that claims the most human lives isn’t an apex predator like a great white shark or a poisonous creature like a snake, but the lowly mosquito. There are, however, several caveats to the increasingly conventional belief that mosquitoes are the deadliest animals on the planet—the biggest being that mosquitoes, all by themselves, aren’t deadly at all.

By itself, the worst thing a mosquito can do to you is make you itch, and it’s not even really responsible for that. When a female mosquito (the males don’t drink blood) sticks its needle-like mouth into a person’s skin, it also releases an anticoagulant to keep it from getting stuck by clotting blood—because if there’s one thing worse than having to stick your mouth into someone’s skin, it’s getting trapped with your mouth in someone’s skin. And it’s not the anticoagulants, but the histamines created by our own bodies in response to this “bug spit,” that cause us to itch. Otherwise we likely wouldn’t notice the effects at all.

What is actually deadly when it comes to mosquitoes are the bacteria, viruses, and parasites these insects carry, and in particular the five types of malaria-causing Plasmodium parasite—P. falciparum, P. vivax, P. ovale, P. malariae, and P. knowlesi—which enter the human bloodstream, reproduce in the liver, reenter the bloodstream, and then begin to systematically kill off blood cells. It’s nasty stuff.

Of the five malaria parasites, P. falciparum is both the most common and the most likely to kill, likely responsible for about 215,000 human deaths annually. That’s about the same number of people who were killed in the atomic bombings of Hiroshima and Nagasaki—but it happens every year. But attacking the parasite itself hasn’t proven a very successful strategy for fighting malaria, especially as P. falciparum has become increasingly resistant to the most common antimalarial drugs, chloroquine and sulphadoxine-pyrimethamine.⁸⁵

“The vector is the Achilles’ heel of the disease,” molecular biologist Andrea Crisanti, one of the world’s foremost experts on combating malaria, told Smithsonian magazine in 2016.⁸⁶ If you attack the pathogen, Crisanti continued, “all you are doing is generating resistance.”

But if you destroy the carrier? Game over.

There are about 3,500 species of mosquitoes. Only about 100 spread disease. And just eight—those belonging to the Anopheles gambiae complex of morphologically identical but reproductively isolated species—are responsible for transmitting the vast majority of malaria cases worldwide.

An increasing number of scientists have come to believe A. gambiae plays no meaningful ecological role in our world, other than spreading disease. They’ve looked. They’ve looked hard. And no one can find a niche this mosquito fills that, were it to simply disappear, wouldn’t be filled by another creature. We’ve driven a lot of animals into extinction through hunting, habitat loss, and human-caused climate change, but some folks are now suggesting these particular blood-suckers, and a handful of other mosquitos that carry deadly diseases, could and should be the first animals humans intentionally eliminate from the face of our planet.

The first time I heard of the idea of intentional extinction was in a 2010 article for Nature by journalist Janet Fang. “Ultimately,” Fang wrote, “there seem to be few things that mosquitoes do that other organisms can’t do just as well—except perhaps for one. They are lethally efficient at sucking blood from one individual and mainlining it into another.”⁸⁷

Fang did find some cautious resistance to such an idea. But not a lot. It turns out that even bioethicists hate mosquitoes. And even if they didn’t, given that we live in a world in which humans are already driving animals into extinction by the thousands, it’s hard to make an ethical case that one species of mosquito is worth millions of human lives.

Conspicuous by its absence in Fang’s article was the fact that, at the time, some people were already at work making the world’s first intentional extinction happen. Indeed, by the time Fang was asking whether it should be done, a group funded by Gates had already taken big steps toward that end on the Caribbean island of Grand Cayman. The Cayman study, which flew under the international radar for more than a year, was intended to see whether the release of male mosquitoes, genetically engineered to be sterile, could reduce the prevalence of dengue fever. And that’s just what happened, according to Oxitec, the UK-based company that ran the trial. Over the course of six months, the company had released more than 3 million sterile males, overwhelming the population of natural, fertile males. That resulted in an 80 percent reduction in the mosquito population—enough to effectively wipe out dengue in a town of around 3,000 residents.⁸⁸

For years scientists had been debating how to carry out such experiments—and the World Health Organization was in the process of drafting guidelines for how such a study should be undertaken.⁸⁹ But Oxitec hadn’t waited for any of that. It argued there was no need to get approval from anyone other than the local government. And with its success as the backdrop for the announcement that it had released genetically modified insects into the wild without informing the international community, the criticism over the company’s actions was rather muted.

And Grand Cayman is, after all, an island. Chances were quite slim that the Oxitec mosquitoes—whose sterility ensured their impact on their own species could only last a generation—would have any effect on the larger world.

It’s for those very same reasons, though, that it wouldn’t be easy to scale up a mosquito eradication program like the one Oxitec first embarked upon in the Caribbean. That process might kill off a lot of mosquitoes in a generation, but not all of them.⁹⁰ To kill all the skeeters, the sterile males would have to be released again and again, across the entirety of a species’ habitat, for each and every mosquito species targeted for elimination.

That’s where gene drive comes in. Instead of pushing a species into extinction, some scientists have now decided, the better solution would be to fundamentally alter it so that it could survive, but in a less dangerous form. In 2015, a team from the University of California at Irvine used the gene-editing-made-easy technique known as CRISPR-Cas9 to genetically engineer mosquitoes that carry P. faciparum–killing antibodies. They further rigged the system so the antibody gene would be supremely dominant, at a passdown rate upwards of 99 percent,⁹¹ ensuring just about every offspring—and their offspring, and their offspring—would be incapable of spreading malaria. Given that the cycle between birth and breeding in mosquitoes takes a matter of days, it wouldn’t take long for such a gene to overwhelm a broad population.

You might think the opposition to completely pushing a species into extinction would be greater than the opposition to changing it, ever so slightly, to make it less dangerous. As it turns out, though, that hasn’t been the case. Whereas a lot of bioethicists seemed rather “meh” on intentional extinction, the opposition to releasing gene-drive-altered insects into the wild has been loud and clear. That’s because even if we were to begin such an experiment on an island, it would be difficult, if not ultimately impossible, to keep it there. Gene-drive modification is like the Energizer Bunny: Once unleashed, it just keeps going and going and going, until an entire species has been wiped out or turned into something else.

To Eleonore Pauwels, one of the world’s most innovative thinkers on the subject of creating “actionable” ethical standards for health and genomic technologies, the dangers are clear. “We now have the power to hijack evolution,” she said in 2016.⁹²

To University of Oxford philosopher Jonathan Pugh, the real danger in “playing God”—by deciding not just whether an animal lives but how it lives—is that “humans are not omniscient and we might overlook the possibility of devastating unintended and unforeseen consequences.”⁹³ And the possibilities that we haven’t overlooked are scary enough.

In 2016, James Clapper, who was then the US director of national intelligence, warned the Senate Armed Services Committee of “far-reaching” national security implications⁹⁴—bioweapons the likes of which were nothing more than a dystopian backstory until just a few years ago. If you can change A. gambiae so it can no longer transmit malaria, after all, there’s not much stopping you from changing it—and thousands of other mosquito species—to carry all sorts of other deadly diseases.

What’s to stop a would-be terrorist, one with a bit of computer science and biology savvy,⁹⁵ from using a mail-order CRISPR gene-editing lab to do just that? The scary answer is: Not much.⁹⁶

And even if those with nefarious aims stay away from the bug-making business, what is to prevent organizations like Oxitec from releasing gene-drive-altered animals into the world, risking unintended consequences? The even scarier answer is: Almost nothing.

Under current international law, each country has a right to choose for itself what biological risks it exposes itself to. Recognizing creatures like mosquitoes don’t pay much heed to international borders, however, many nations have signed on to the Cartagena Protocol on Biosafety, which governs transboundary movement, transit, and handling, and the use of “living modified organisms.”⁹⁷

But it’s no coincidence that when scientists sought to release Wolbachia-infected mosquitoes in an attempt to control dengue fever and chikungunya (the Wolbachia bacterium kills off offspring during embryonic development) they chose Queensland, Australia, to do it. Australia wasn’t a signatory to the protocol.

As any fan of the TV series Dexter can attest, it’s awfully hard to root against a killer of killers. Is it really so bad for scientists to go “venue shopping” when all they’re trying to do is find countries where there are fewer hurdles to wiping out deadly diseases?

Maybe not. But how deadly does something have to be in order for us to forgive a little ethical flexibility?

If we’re willing to overlook the overlooking of international standards when it comes to mosquitoes, what about freshwater snails, which transmit parasitic flatworms that cause schistosomiasis, resulting in an estimated 200,000 deaths per year, according to the World Health Organization? How about snakes, which kill 100,000 or more people each year? And what of dogs, who are responsible for up to 60,000 human deaths per year, mostly through the transmission of rabies?

How many organisms are we willing to change, at a genetic level, to protect ourselves? How will we decide which genes are best suited for the task? And who gets to choose?

How we answer these questions when it comes to the world’s deadliest organisms will directly inform our relationship with Mother Nature for the rest of history.

Soon we’ll have to choose. I sure hope we choose wisely.