The success of snakes is down to remarkable internal re-engineering (Image: Joel Sartore/NGC/Getty Images)
Losing legs was just the start of snakes’ bizarre journey – to switch from barely being alive to eating an antelope takes re-engineering at the molecular level
SNAKE! Just the thought is enough to trigger a spasm of fear in many of us. Snakes make biologists’ hearts beat faster, too, but for a different reason: in evolutionary terms, they may be the most surprising group of vertebrates on Earth.
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Their long, legless bodies, it turns out, are the least remarkable thing about them. It’s on the inside that snakes have made extraordinary changes. They have pared down their internal organs, mostly eliminating one lung and all but one lobe of the liver. They have evolved a novel heat-detecting sense organ and the most sophisticated venom system of any animal, and they can turn their metabolism up and down more dramatically than any other vertebrate. This re-engineering even extends to the molecular level – proteins that have remained unchanged across other vertebrates have been rebuilt in snakes.
“It looks like evolutionarily, snakes are a kind of redesigned organism,” says Stephen Mackessy, who studies snakes at the University of Northern Colorado in Greeley. And with the help of the first two snake genomes to be sequenced, we are beginning to piece together their remarkable evolutionary journey.
The story of how snakes evolved begins just over 100 million years ago, with a lizard or lizard-like reptile. Biologists are still debating about exactly which group the ancestor of snakes belonged to. A few think snakes are descended from the marine reptiles known as mosasaurs, but they are in the minority. “I think the great bulk of the evidence points to a terrestrial origin for snakes, and even a burrowing or secretive origin,” says Harry Greene, an evolutionary biologist at Cornell University in Ithaca, New York.
The mainstream view is that proto-snakes belonged to a group whose living representatives include the monitor lizards and Gila monsters. So why did some members of this group lose their legs and elongate their bodies? Most likely it was to chase insects through subterranean burrows or tangles of grass. Indeed, the most primitive snakes found today – a group called the blind snakes because of their vestigial eyes – still live underground feeding on ants and termites, supporting the notion that the earliest snakes might have been burrowers.
Acquiring a snake-like body involved surprisingly few mutations. The “grow limbs here” genes are still active in snake embryos, says Michael Richardson, a developmental biologist at Leiden University in the Netherlands, but the cells in these areas just ignore the signal, so no legs form. Snakes get their long bodies by budding off vertebrae at an unusually fast rate as embryos, so that they end up with many more than other animals – over 500 in some species.
In fact, it appears to be really easy for lizards to evolve a snake-like body, as it has happened on numerous occasions. “There are dozens of lizard lineages that have lost their limbs, ” says Michael Lee, an evolutionary biologist at the South Australian Museum in Adelaide. Most, however, are small burrowers, seldom seen and little studied.
Extraordinary abilities
The ancestors of snakes, by contrast, slithered back above ground and started to hunt larger prey, eventually giving rise to fearsome predators such as rattlesnakes and cobras. There are around 3400 species of snake today, found everywhere except in the coldest polar regions. Some have colonised tropical seas, and never touch dry land. Others, like boas and pythons, have grown very large – although even the biggest snakes living today are small compared with , an extinct snake that grew to more than 10 metres in length and weighed over a tonne. No other group of legless lizards is as diverse and widespread. “None of them are as successful as snakes,” Lee says.
What makes snakes special, then, are the less obvious changes that occurred after their ancestors lost their legs. In particular, snakes have some extraordinary metabolic abilities. These started to evolve very early on; blind snakes – which branched off early in snake evolution – show extensive changes to their mitochondrial genes that may have allowed proto-snakes to burn less energy by turning down their metabolism.
This paved the way for the very effective strategy early snakes adopted as they moved back above ground: eating occasional big meals rather than lots of little ones. As a result, snakes don’t have to spend all their time hunting – when they are vulnerable to being preyed upon themselves – and can cope with times when food is scarce.
For an animal that swallows its prey whole, though, eating large meals is a challenge. Their remarkable ability to swallow prey much larger than their heads required extensive changes. The skin around their mouth is unusually folded, for instance, allowing it to expand much further than that of most animals, says David Cundall of Lehigh University in Pennsylvania. And in the jaws can stretch so much that the interlocking actin and myosin proteins are ripped apart from one another, then gradually return to their normal positions after feeding.
The metabolic adaptations of snakes are even more dramatic. Between meals, for instance, the Burmese python goes into almost complete shutdown, reducing its resting metabolic rate to the lowest level known in any vertebrate. “When snakes are idling, the idle is extremely slow,” says Todd Castoe of the University of Texas at Arlington. “The difference in metabolism between a live snake and a dead snake is minimal.” This means large snakes can go many months without a meal.
“The difference in metabolism between a live snake and a dead snake is minimal”
Metabolic marvels
When, say, a python swallows an antelope, though, everything changes. Now the race is on to digest the huge meal. Within days of feeding, a python’s small intestine and liver double in mass and its kidneys and heart also increase greatly in size, while its metabolic rate increases up to 45-fold (see diagram). That’s about the same metabolic ramp-up as seen in a racehorse sprinting in the Kentucky Derby, says Castoe. “But that’s running flat out across the field. When snakes are at their peak, they are motionless.”
This frantic activity continues for several days. Within two weeks, its meal fully digested, the snake shuts everything down again.FIG-mg29720701.jpg
What made these metabolic feats possible? Castoe is a member of the team that last year completed the first two snake genome sequences, belonging to the Burmese python and the king cobra. By comparing these genomes with those of other vertebrates, they were able to work out which genes had changed and when, and look for the fingerprints of natural selection.
What they found was astonishing. Of 7442 genes common to all land vertebrates, 772 had changed as a result of natural selection. And the vast majority of those changes – 516 of them – were present in both species, meaning they occurred more than 80 million years ago, before pythons branched off from the lineage leading to cobras.
Changes to a few hundred genes might not seem much, but it is an extraordinary number given that most genes are involved in basic processes that vary little from species to species. “It’s somewhere around an order of magnitude more than we’re used to,” says Castoe. He thinks that these extensive changes are what allow snakes to ramp their metabolism and their organs up and down as required. That remains to be proven, but many of the genes concerned are indeed involved in metabolism and organ development.
Indeed, a few years ago, Castoe found that snakes had even tinkered with one of the “untouchables” of evolution: a protein called cytochrome oxidase I, which enables cells to “burn” food to produce energy. “It’s the reason you breathe oxygen,” says Castoe. Parts of this protein have remain unchanged in most organisms for a billion years, yet snakes have . Castoe has not yet shown whether these changes contribute to snakes’ metabolic superpowers, but he thinks it is very likely.
Of course, being able to ramp up your metabolism to cope with huge meals is one thing; catching those meals in the first place is quite another. One branch of the snake family evolved a very effective way to deal with large prey: venom.
It’s not clear exactly when venom first evolved. Based on similarities between venom proteins, of the University of Queensland in Brisbane, Australia, has suggested that the ability to make venom evolved around 200 million years ago in a lizard ancestor of snakes and modern venomous lizards. If so, early snakes may have had venomous saliva, which could enter their victims’ blood through the puncture holes made by ordinary teeth. Other biologists, however, think the protein similarities Fry found may be the result of convergent evolution rather than a common origin, and that venom has evolved separately on several occasions.
What’s clear is that the sophisticated fangs found in most venomous snakes today evolved some time after 80 million years ago, which is when the non-venomous boas and pythons branched off from the ancestor of vipers, cobras and other venomous snakes. This ancestor evolved rear fangs with grooves along which venom could flow. In some snakes these fangs moved forward in the mouth and the grooves deepened, eventually giving rise to hollow teeth resembling hypodermic needles, along with a muscular system for pumping venom through them.
Freek Vonk, an evolutionary biologist at the Naturalis Biodiversity Centre in Leiden, the Netherlands, and his colleagues have been studying snakes’ venom as well as their fangs. They identified venom genes in the cobra, then looked to see which genes were most closely related in the Burmese python and the anole lizard. To their surprise, they found that : most of the 20 families of genes that code for toxins are related to genes that perform day-to-day housekeeping functions within cells.
These day-to-day genes also tend to be active at low levels in all tissues. “That means when you make a new gland, the odds are good that the gene will be expressed there,” says Castoe, who was also part of the team. Sometimes snakes simply hijacked the gene, converting it to a new, venomous function. More often, though, the original gene was duplicated, often many times, giving snakes lots of spare proteins to experiment with and turn into deadly toxins.
The result is that the venom of most advanced snakes is a fantastically complex mix of toxins – more than 100, by some counts – that varies depending on species, locality and sometimes even between individuals of the same species. All this diversity helps snakes keep ahead in the evolutionary arms race: if snakes had just a single toxin, it would be easier for their prey (and predators) to evolve resistance.
“Snake venom can be a fantastically complex mix of more than 100 toxins”
Not every component of venom is there primarily to kill prey or defend against predators, though. Many snakes, especially rattlesnakes, have venoms rich in toxins that break down the tissues of bitten animals. This helps rattlesnakes, which eat unusually large prey, win the race between digestion and rot, says Mackessy. In addition, Mackessy recently discovered that one component of rattlesnake venom, a toxin called crotatroxin that inhibits blood clotting, also serves as a scent trail that helps the snake locate bitten animals after they die.
All this is only the beginning. Castoe, Vonk and their colleagues are already working to sequence more snake genomes. At the top of their list are a blind snake – of interest because of its resemblance to early snakes – and the Malayan pit viper, with its infrared sense (see “Seeing through closed eyes“). These two genomes should cast further light on the origin and evolution of the many adaptations that make snakes such unusual and fascinating organisms. “The potential for unlocking the secrets of snake biology is just huge,” says Green.
Seeing through closed eyes
Even as the first snakes were gaining some extraordinary abilities, they lost others. During the millions of years that the small, burrowing proto-snakes lived underground, their eyelids fused shut and their eyes degenerated. When early snakes moved back above ground, they had to cobble together working eyes from what was left. They had lost a special structure for nourishing the retina, so – but these pass in front of the retina, obscuring vision.
Proto-snakes also lost the ability to focus images by changing the shape of the lens. Their descendants instead evolved a way of focusing by moving the lens back and forth within the eyeball, much as Sherlock Holmes moves his magnifying lens to focus on a clue.
The fused eyelids – called spectacles – have remained firmly shut to this day. Instead, they have become almost completely transparent. With no proper eyelids the spectacles are easily scratched, but they are renewed when the skin is shed.
Another problem is that there are blood vessels running through the spectacles. Last year it was shown that , presumably to give the animals clear vision when it is most needed.
While snakes’ eyesight is probably not as good as it might otherwise have been, their other senses are highly developed. Some can even “see” in the infrared thanks to special heat-sensing pits on their faces.
One antivenom to cure them all
If you get bitten by a venomous snake, a dose of antivenom containing antibodies that neutralise the toxins could save your life. But which antivenom will work? Many snakebite victims don’t know which snake bit them, so drug companies produce cocktails of antivenoms that work against several species. This is expensive, however, and increases the chance of an allergic reaction.
Nicholas Casewell and his colleagues at the Liverpool School of Tropical Medicine in the UK think there is a better way. They are using genetics to identify regions of venom proteins that are the same in different snake species. They then design antibodies to bind to these regions, meaning each antibody should be effective against the bite of several snake species. The ultimate result should be cheaper and safer antivenoms.
This article appeared in print under the headline “Under the hood”
