Snakes' extreme metabolic feats may yield human treatments

TUSCALOOSA, ALA. – On a cold, gray winter day, Stephen Secor pulled into the driveway of David and Amber Nelson, who welcomed him into their basement filled with stacks of refrigerator-size, glass-doored cages. Each contained a massive snake. Some of the pythons and boa constrictors were adoptions from Secor's lab, a few miles to the west at the University of Alabama.

Secor and David Nelson, a product manager at a car parts factory, hoisted the snakes one at a time out of their cages.

"Monty's a good snake, aren't you?" Secor asked a tan Burmese python as it slithered up his shoulders.

It was feeding day. The snakes had not eaten for two weeks. They were now about to perform one of the most extraordinary acts of metabolism in the animal kingdom — a feat that Secor has been exploring for a quarter of a century.

He has been finding adaptations throughout the snake's body, such as the ability to rapidly expand organs and then shrink them. His findings offer tantalizing clues that might someday be applied to our own bodies as medical treatments.

Pythons and several other kinds of snakes regularly eat a quarter of their body weight at once, sometimes gulping down whole animals. Sometimes a meal will outweigh them.

Secor started studying how these snakes alternate between fasts and feasts in graduate school. These days, he is collaborating with genome experts to investigate the animals in molecular detail. The scientists are finding that snakes perform a genetic symphony, producing a torrent of new proteins that enable their body to turn into an unrivaled digestion machine.

"They're taking state-of-the-art genomics and pushing the boundaries on what we can understand," said Harry Greene, a Cornell University snake expert. "It's not too preposterous to imagine that could have fantastic human health implications."

When Secor came to the University of California, Los Angeles, he decided to find out how much energy snakes needed to digest a meal. "In two days, I had these numbers that made no sense," he said. When mammals feed, their metabolic rate goes up 25% to 50%. The rattlesnakes' jumped about 700%.

Secor then found that pythons reached even greater extremes. If a python eats a quarter of its body weight, its metabolic rate jumps 1,000%. But pythons can eat their whole body weight if Secor has enough rats on hand. In those cases, their metabolic rate can soar by 4,400%, the highest recorded for an animal.

For comparison, a horse in full gallop increases its metabolic rate by about 3,500%. But whereas a horse may gallop for a couple of minutes in the Kentucky Derby, a python can keep its metabolic rate at its extreme elevation for two weeks. Secor has spent years investigating what the snakes are doing with that extra fuel. For one thing: making stomach acid.

We add some acid to our stomach a few times a day to handle our regular meals. But when a python is fasting, its stomach contains no acid. Its pH is the same as water. Within hours of swallowing an animal, Secor found, a snake produces a torrent of acid that will remain in its stomach for days, breaking down the snake's prey.

Meanwhile, the snake's intestines go through a remarkable growth spurt. Intestinal cells have fingerlike projections that soak up sugar and other nutrients. In a snake, those cells swell, their fingers growing five times longer. A python can triple the mass of its small intestines overnight.

Secor and his colleagues have found that the rest of a snake's body responds similarly. Its liver and kidney double in weight, and its heart increases 40%.

By the time a rat makes it to the end of the large intestines, all that remains is a packet of hair. Everything else will be coursing through the snake's body. In the meantime, its gut will shrink, its stomach will turn watery again and its other organs will return to their previous size.

From an evolutionary point of view, Secor could see how this drastic reversal made sense. "Running all this stuff is a tremendous waste of energy," he said. "Why keep things up and running when you don't use them?" But how snakes managed this feat was harder for Secor to explain. Other scientists couldn't help him.

Then in 2010, Secor met Todd Castoe, an expert on sequencing reptile DNA. "The metabolism is crazy — so much of this is extreme and unexpected," said Castoe, who teaches at the University of Texas at Arlington.

Castoe and Secor started a collaboration to understand snakes at the molecular level. In 2013, they published the genome of the Burmese python. Now they had a catalog of every gene that snakes might use during digestion.

Since then, the scientists have tracked how the snakes use these genes.

The researchers were shocked to find that within 12 hours of its swallowing prey, a vast number of genes become active in different parts of a snake. "You might expect maybe 20 or 30 genes to change," Castoe said. "Not 2,000 or 3,000."

A number of the genes are involved in growth, the researchers have found, while others respond to stress and repair damaged DNA. It is a strange combination that scientists have not seen in animals before. Castoe speculates that snakes use their growth genes far more intensely than, say, a growing human child would.

That overdrive allows the snakes to double the size of organs in a matter of hours and days. But it may also come at a cost: The cells are growing and dividing so fast that they produce a lot of malformed proteins that damage the cells.

When the swollen organs shrink back to normal, it appears that the snakes may simply shut down their repair genes, so that their cells are no longer shielded from their self-inflicted damage. "The whole growth thing collapses," Castoe speculated.

The scientists suspect that the snakes orchestrate their transformation with a few molecular triggers. Some genes may cause many other genes to switch on in an organ and make it grow. If scientists could find those triggers, they might be able to regenerate damaged tissue in people.

Alternatively, doctors might mimic the way that snakes rapidly — but safely — reverse their growth. There might be clues in their biology for how to stop the uncontrolled growth of cancers. "If you knew the answers to all that, you'd probably have drugs that could cure dozens of diseases," Castoe said.