The mystery started with some skin samples. Anura Rambukkana was a Ph.D. student in Amsterdam, analyzing biopsies from migrants with Hansen’s disease, or leprosy. The illness could be painful and disfiguring, but in the lab, the infected cells didn’t look sickly. To Rambukkana’s eye, they seemed to be doing great.
He noticed the same thing with nerve cells from mice. When he infected them with Mycobacterium leprae, they didn’t just look OK; they actually looked better than their uninfected counterparts. They were brighter, and proliferating more vigorously, as if the pathogen had somehow made them more youthful. The analogy wasn’t far off: These cells’ molecular profile turned out to be almost embryonic, primordial, resembling the body’s shape-shifting materials before they’ve been assigned a specific role. They looked like stem cells.
That discovery was published in 2013, to some fanfare. “Bacteria’s hidden skill could pave the way for stem cell treatments,” trumpeted one press release. But the “could” was doing a lot of work in that sentence. Sure, the bugs had performed a strange feat akin to turning back the clock — but that was in a lab dish. “Are they going to do a similar kind of reprogramming in the real world?” Rambukkana wondered.
Nearly 10 years later, he’s found that the answer is yes. In a paper published Tuesday in Cell Reports Medicine, he and his colleagues report that the bacteria can expand the livers of armadillos, spurring the growth of healthy tissue without showing signs of scarring or cancer. Left for longer, the pathogen would eventually cause issues. But, as Rambukkana, now a professor at the University of Edinburgh, explained, “during the establishment of infection, this beauty is happening.”
His interest is more than just aesthetic, though. With enough time or alcohol or fat or viral hepatitis, our own livers can become sclerotic, unsalvageable, leaving little option besides transplant. Rambukkana hopes his finding might unlock some bacterial regenerative secret. Again, though, the “might” is doing some heavy lifting. “A bacterium that can provoke healthy liver growth — albeit in a very exotic animal — to me, that’s quite exciting,” said Scott Friedman, chief of the division of liver diseases at the Icahn School of Medicine at Mount Sinai, who wasn’t involved in the new study. “But we can’t really say for sure that this is relevant to human livers.”
He also couldn’t help but wonder: Why armadillos?
The nine-banded armadillo has many admirable traits. It looks like an anteater in a knight errant’s suit, its armor gray, with whitish wisps of hair poking out. Its burrows are sturdy enough to be used secondhand by skunks, possums, snakes, and owls. Its meat, the “Joy of Cooking” tells us, is “light” and “pork-like.” For the purposes of leprosy research, though, its real charm lies in its body temperature.
In humans, the bacteria try to stick to the extremities, with their cooler climes. Armadillos generally run cold. Besides us, they’re one of the few animals that M. leprae likes to infect — a useful tool for studying a bug that doesn’t grow well in the usual lab-dish setup for rearing bacteria. If you want samples, your best bet is an armadillo-raising institute in Baton Rouge, La., which extracts the bacilli from the animal’s liver.
After his 2013 paper, Rambukkana put in a call to the institute. He’d seen how the bug could prod host cells into leaving behind their adult identity. To him, that looked like a bacterium reshaping its microscopic environment for its own purposes. It could hide out in nerve tissue to evade an immune response — but at some point, it wanted more room. It couldn’t survive outside of cells, making solo travel difficult. Perhaps it was reprogramming them so that they’d shape shift and then migrate, to join other tissues. He wanted to know if that kind of radical home redecorating was going on in live animals, too. Since the bug used in labs around the world was being centrifuged out of armadillo liver purée, he wondered if those organs held a clue.
The person he called was Richard Truman, then the chief of research for the National Hansen’s Disease Program. Had Truman noticed anything about the armadillo livers? Might they be enlarged at all?
Yes, Truman said, in fact, they were enlarged. But he hadn’t thought much of it. Organs often get bigger with infection, immune cells gathering, flocking to important battlegrounds. It wasn’t just the livers. The spleens might go from 5 grams to 55, Truman said. The lymph nodes, normally about as big around as a pinky tip, could swell to the size of a golf ball.
“In the case of the armadillo, M. leprae is just such a very unusual organism that it can grow into such massive numbers in the host without causing much overt pathology,” Truman explained in an interview. “And it really doesn’t dissuade the armadillo, it doesn’t slow them down. It doesn’t really make them ill until just the very, very last stages of the infection.”
When Rambukkana’s team examined the infected livers, though, the enlargement didn’t appear to be the product of an immune response. Rather, some of the genes called into action were those turned on during embryonic development. These weren’t stem cells per se, but they resembled stem cells, similar to the ones that built the liver’s architecture in the first place, a rich warren of blood vessels and hepatocytes and bile ducts.
How this fits into our own liver landscape — if at all — remains to be seen. “We have known since the Greeks” — think Prometheus, his liver eternally being eaten out by an eagle — “that the liver has a really exquisite capacity to regenerate,” said hepatologist Rotonya Carr, division head of gastroenterology at the University of Washington.
That exquisite capacity is why you can give away some of your liver for transplantation. Cut off two-thirds of it, and those two-thirds will grow back. That may also be why it can take decades for liver damage to accrue. “All the time the liver is being injured, it’s mounting a regenerative response, trying to break down scar, trying to restore the normal architecture,” said Friedman. After 20 or 30 years of viral infection or alcohol use or fatty buildup, the restoration crew gets exhausted, and the scarring begins to win out.
The precise workings of this regeneration remain a mystery; the ability to use it to our own therapeutic advantage feels even farther off. To Carr, this armadillo research could open up a new, if wacky, avenue. If you cut off a bit of liver in a lab mouse, it’ll grow back to its original size and stop. “In the setting of chronic liver injury, we actually probably do want the liver to grow back beyond its pre-regeneration size,” explained Carr — to extend beyond the scarred old tissue, to produce something new and functional, the way M. leprae does in these animals.
That does not mean that Rambukkana wants to inject people with leprosy-causing bacteria, no matter how treatable Hansen’s disease is with antibiotics. What’s next on his agenda is to understand how M. leprae is extending the liver. Which genes are being called into action? Which proteins are involved? Maybe somewhere in there lies the source ingredient for a potential drug.
It won’t be the first attempt to harness the liver’s regeneration skills. “I can tell you that every decade there seems to be a new magic tonic,” Friedman said. He’s been in the business 35 or 40 years. So far none of them has panned out. Then again, this is the first he’s heard about looking to armadillos.
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