Sunday 28 June 2020

Eat Rat, Make New Body: Easy Stuff for Pythons - The extreme metabolism of some snakes could provide leads on how to regenerate human tissue. via Herp Digest

By Carl Zimmer, Photographs by Wes Frazer, New York Times, 5/12/15
 TUSCALOOSA, Ala. — On a cold, gray winter day, Stephen Secor drove to the outskirts of town to catch up with some old friends. He pulled into the driveway of David and Amber Nelson, who welcomed him into their converted basement, filled with stacks of refrigerator-size, glass-doored cages. Each cage contained a massive snake. Some of the Nelsons’ pythons and boa constrictors were recent adoptions from Dr. Secor’s lab, a few miles to the west at the University of Alabama.
 Dr. Secor and Mr. Nelson, a product manager at a local car parts factory, hoisted the snakes one at a time out of their cages.
 “Hello, Monty, how’s my sweetheart?” Dr. Secor asked a tan Burmese python as it slithered up his shoulders. “Monty’s a good snake, aren’t you?”
“Oh yeah,” Mr. Nelson said, as if he was referring to his toy Pomeranian upstairs. But Mr. Nelson never let his guard down, even as he let another snake flick its tongue over his eyebrow. “Any of these could kill you if you let it,” he said, somehow cheerfully.
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 Dr. Secor has been exploring for a quarter of a century.
He has been finding adaptations throughout the snake’s entire body, such as the ability to rapidly expand organs and then shrink them back down. His findings offer tantalizing clues that might someday be applied to our own bodies as medical treatments.
Mr. Nelson opened the cage that held a dark gray Burmese python named Haydee, and heaved in a large rat.
The rat stood frozen in the corner, but Haydee ignored her new roommate for several minutes. She slowly raised her metallic-colored head, indifferently flicking her tongue. And suddenly Haydee became a missile.
She shot across the cage, snagged the rat with her upper teeth and wrapped her thick midriff around her victim. Between Haydee’s coils, the upended rat was still visible, its back legs and tail jerking in the air. It heaved for a while with rapid breaths, then stopped.
Haydee loosened her grip and raised her head to the door, as if wondering if more rats were in the offing. Then she turned back to her prey, nose to nose, and opened her mouth wide.
 She used her side teeth to pull her head over the dead rodent. Her jaws stretched apart to make room, and she worked the rat into her expanding throat. She arched her head up toward the door, as if offering her human audience a chance to say farewell to the rat as its hind legs and tail slid into its esophagus.
But Haydee’s performance was far from over. Pythons and several other kinds of snakes regularly eat a quarter of their body weight at once. Sometimes a meal will outweigh them. Over the next few days, they break their prey down and absorb almost all of it.
Dr. Secor started studying how these snakes alternate between fasts and feasts since graduate school, and has been developing new ways to study them. These days, he is collaborating with genome experts to investigate the animals in molecular detail. Together the scientists are finding that snakes perform a genetic symphony, producing a torrent of new proteins that enable their body too quickly turn into an unrivaled digestion machine.
“I am a huge fan — 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 who is not involved in the project. “It’s not too preposterous to imagine that could have fantastic human health implications.”
As a graduate student, Dr. Secor studied how sidewinder rattlesnakes survived as they went from long fasts to gulping down whole animals. He wondered how much energy they needed to digest a meal.
When he came to U.C.L.A. as a postdoctoral researcher, he decided to find out. He fed mice to his rattlesnakes and then put them in a sealed box. He could analyze samples of air from the box to track how much oxygen they breathed to burn fuel.
“In two days, I had these numbers that made no sense,” he said.
When mammals feed, their metabolic rate goes up between 25 and 50 percent. The rattlesnakes jumped about 700 percent.
Dr. Secor switched to pythons and found that they reached even greater extremes. If a python eats a quarter of its body weight, its metabolic rate jumps 1,000 percent. But pythons can eat their whole body weight if Dr. Secor has enough rats on hand. In those cases, their metabolic rate can soar by 4,400 percent, the highest ever recorded for an animal.
For comparison, a horse in full gallop increases its metabolic rate by about 3,500 percent. But whereas a horse may gallop for a couple minutes in the Kentucky Derby, a python can keep its metabolic rate at its extreme elevation for two weeks.
Dr. Secor has spent years investigating what the snakes are doing with all 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 at all. Its pH is the same as water.
Within a few hours of swallowing an animal, Dr. 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. Suddenly its digestive tract can handle the huge wave of food coming its way.
Once all that food is circulating through the snake’s bloodstream, its other organs have to cope with it. Dr. Secor and his colleagues have found that the rest of a snake’s body responds in a similarly impressive fashion. Its liver and kidney double in weight, and its heart increases 40 percent.
By the time the rat in Haydee’s esophagus makes it to the end of her large intestines, all that remains is a packet of hair. Everything else will be coursing through her body, much of it destined to end up as long strips of fat. In the meantime, her gut will shrink, her stomach will turn watery again and her other organs will return to their previous size.
From an evolutionary point of view, Dr. 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 Dr. Secor to explain. Other scientists couldn’t help him.
When he showed pictures of shrinking snake intestines to pathologists, they were baffled. “They’d say, ‘Your animals are sick. They’re dying. They have parasites that are ravaging their intestines,’” Dr. Secor said. “I’d say, ‘No, they’re healthy.’ They just shook their heads and sent me on my way.”
Measuring their oxygen intake and looking at their intestines under microscopes could only take Dr. Secor so far. He asked colleagues who studied DNA what it would take to track how snake genes turned on and off during digestion.
“And they’d say, ‘You couldn’t do it,’” Dr. Secor recalled. “It would take years and years and years, because you’d have to pull each one out, and then you have to find out what it was.”
Then in 2010, Dr. Secor met Todd Castoe, an expert on sequencing reptile DNA, who jumped at the chance to help Dr. Secor make sense of his snakes.
“The metabolism is crazy — so much of this is extreme and unexpected,” said Dr. Castoe, who now teaches at the University of Texas at Arlington.
Dr. Castoe and Dr. Secor launched a collaboration to understand snakes at the molecular level. In 2013, they and their colleagues 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. Dr. Secor and his students dissect snakes either during a fast or after they have had a meal. The researchers examine every organ and preserve samples for later study.
 “Everything is pickled or frozen,” Dr. Secor said.
He ships some of the material to Dr. Castoe in Texas, who cracks open the snake cells. Dr. Castoe’s team then finds molecular clues to which genes are active in different organs.
The researchers were shocked to find that, within 12 hours of 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,” said Dr. Castoe. “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. Dr. 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 don’t have time to be careful. Along the way, 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,” Dr. Castoe speculated.
Even among snakes, the fast-and-feast way of life is unusual, having independently evolved only a few times.
By looking at other such fasting snakes, the scientists have found some of the same changes in gene activity. They are focusing on this smaller set of genes.
“It’s like we’re cutting away pieces of the pie, and we just want the juiciest part,” said Dr. Castoe.
If he and Dr. Secor can figure out what happens in snakes, it might be possible to elicit some of their powers in our own bodies, since we share many genes in common with animals.
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,” Dr. Castoe said.
But Dr. Castoe sees a lot of work ahead before any such benefits emerge. For now, he and his colleagues have no idea what the triggers are in snakes.
To find out, they are now looking at snakes within just a few hours of catching prey. They can see changes in the snake cells. But those changes occur too quickly to be the result of switching on genes. It is possible that the snakes are refolding the proteins that already exist in their cells, so that they do new things.
“I’d love to put together the whole pathway,” Dr. Secor said. “But we’re not even close to figuring this all out.”

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