Photograph by Jim Collins, Ana Vieira and Phillip Newmark
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A scanning electron micrograph of a male and female Schistosoma mansoni
Photograph by Jim Collins, Ana Vieira and Phillip Newmark

The Parasite’s Fountain of Youth

In 1980, a man walked into the Royal Perth Hospital in Australia, complaining that he was tired. He had been tired at that point for two years. The man’s medical history offered no good clues–at 44, his only indulgence was a glass of white wine at dinner each night. His doctors pushed and poked until they discovered his liver was swollen. Yet he showed none of the symptoms you’d expect from cirrhosis or liver cancer. The cause of the man’s trouble only became clear when the doctors got the report on his stool. It contained eggs from an animal known as Schistosoma mansoni–otherwise known as the blood fluke.

Blood flukes are parasitic flatworms. They get their start living in snails, which shed the parasites into the surrounding water. If you go wading into a blood fluke-infested pond, the missile-shaped flukes will sniff their way to your skin and drill in. Once they reach a blood vessel they surf the sanguine tide until they reach your intestines. They take up residence in the blood vessels there, producing eggs that they nudge into the intestinal walls. The eggs get washed out of the body with their host’s stool, perhaps to infect a freshwater snail. Sometimes, however, the eggs get swept off in the wrong direction and wind up in the liver, where they cause chronic inflammation.

Getting blood flukes (the disease is known as schistosomiasis or bilharzia) is, sadly, nothing special. Two hundred million people suffer from infection with Schistosoma mansoni or a related species of blood fluke, Schistosoma haematobium. But the case of the man at the Royal Perth Hospital was singular in one respect. In order to get infected with blood flukes, you have to go to the places where its snail hosts live. And Australia is not one of those places. The man had, in fact, traveled to East Africa, where the blood flukes are common. But he hadn’t been there in 31 years.

This was remarkable, and more remarkable than you might think. It didn’t mean that the blood flukes had taken up residence in the man’s body and had produced 31 years of new generations. Remember, the eggs cannot develop inside a human body. They have to reach fresh water to hatch, and if they can’t find a snail to invade, they die. The tired man in Australia had been carrying the same blood flukes with him that he had picked up in Africa. These parasites were themselves at least 31 years old.

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Male and female blood flukes.

The many years that a blood fluke can spend in a human host are striking, and all the more striking the more you contemplate how they spend those decades.  Most species of flatworms are hermaphrodites, with both eggs and sperm. Blood flukes are either male or female. The females are thin and small. The males are larger, shaped like a canoe. At one end of their body, they had a mouth for drinking blood and a giant sucker. In their human host, female blood flukes select their mates and fit themselves into the trough of the male’s body. There they will remain, getting nourishment from their mate, along with the sperm necessary to produce their eggs. Blood flukes will spend years in this monogamous union, although sometimes they will get divorced and seek a new mate.

In all that time, the blood flukes manage to survive inside enemy territory. These are not microscopic creatures; they can get to be a centimeter long. Yet the immune system of their host typically ignores adult blood flukes. How they manage to escape notice–instead of getting rejected like a transplanted organ–isn’t yet clear. The parasites probably evade destruction by producing camouflage in the form of human-like proteins.

But blood flukes may have another source of longevity. It turns out that inside their bodies is a kind of fountain of youth.

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Free-living flatworm.

This discovery is the work of Philip Newmark of the University of Illinois and the Howard Hughes Medical Institute and his colleagues. Newmark–like many other scientists–has spent years studying free-living cousins of blood flukes called planarians. Planarians can reproduce in a manner that seems to defy the rules of zoology. They simply split in half, and each half then regrows the rest of its body.

Scientists can regrow new planarians from tiny cuttings, complete with muscles, intestines, nerves, and the many other organs that are necessary for a full-blown flatworm. We’ve known about this power of regeneration for centuries, but it always bears appreciating anew. Imagine that someone cut off your ear and tossed it on the ground, where it promptly grew into a complete copy of yourself–complete with a new brain.

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Flatworm amputations

This power makes planarians an object of fascination for cell biologists. They’ve searched these flatworms for the secrets of their renewal. It appears that their bodies are sprinkled with unusually flexible stem cells called neoblasts. These cells can travel the planarian body to wherever they’re needed. Once they arrive, they start dividing quickly and differentiate into any tissue the planarian requires.

Our bodies can also regenerate themselves, albeit on a far more modest scale. As adults, we carry small collections of stem cells that can produce new tissues. They heal a gash by producing new skin cells. In the intestines, they produce new lining to replace sloughed-off cells. Stem cells in bone marrow rejuvenate our blood supply. Stem cells may also be important to the workings of the brain. But in these cases, the stem cells have only a narrow scope. They can only develop into a few cell types. We can regenerate skin and even a lobe of our liver, but we can’t regrow an eye or a hand. Studying planarians allows scientists to discover some of the signaling molecules that might be able to trick our own stem cells into more dramatic rebirths than they can manage on their own.

Newmark and his colleagues asked themselves one of those questions that seems so obvious in hindsight that you have to wonder why no one asked it before. Given that planarians and blood flukes are cousins, do blood flukes have this same power of regeneration? It’s an easy question to ask, but a vexingly hard one to answer. Planarians live cheerfully in a lab tank, but blood flukes require snails and mammals to complete their life cycle. Newmark and his colleagues have helped make it easier to study blood flukes in recent years; for example, they’ve developed a toolkit of molecules they can apply to blood flukes to probe their cells.

The neoblasts in planarians are constantly dividing. So Newmark and his colleagues started their search for similar cells in blood flukes by looking for signs of proliferation. As a cell multiplies, it makes DNA, and chemists have found that a compound called EdU can get taken up in the structure of new DNA. Newmark and his colleagues doused blood flukes with EdU and then inspected the parasites under a microscope to see if any cells had taken it up. They found proliferating cells sprinkled throughout the blood fluke body.

Newmark and his colleagues teased out some of the multiplying cells and gave them a closer look.  They bore a striking resemblance to neoblasts, not just in their structure, but in the activity of their genes. All these clues pointed in the same direction: the proliferating cells in the blood flukes seemed a lot like neoblasts from planarians.

To watch these cells in action, the scientists infected mice with blood flukes. Then they injected the mice with EdU, which the parasites took up in their proliferating cells. Those cells then migrated through the body of the blood flukes. Some headed to the intestines of the parasite, while others headed to the muscle. There the cells divided into new cells, rejuvenating both kinds of tissue.

Newmark and his colleagues conclude that blood flukes have flexible stem cells akin to the neoblasts of planarians. It’s possible, they suggest, that these stem cells help blood flukes live so long. They may rejuvenate the parasites after they’ve been attacked by the immune system, or allow them to recover from a dose of anti-schistosome medicine. And as the blood flukes get old, the cells can be a fountain of youth, rejuvenating their tissues.

If these cells are indeed important to blood flukes, then we would do well to learn how to manipulate them. Newmark and his colleagues noticed that one of the genes switched on in the neoblast-like cells belongs to a family of signaling genes that are important to keep stem cells multiplying. They figured out how to make a drug that blocks that gene in blood flukes. In the drugged parasites, the neoblast-like cells slowed down.

If these flexible stem cells really are essential to the longevity of blood flukes, then this drug could be a powerful weapon against them. To fight against some parasites, we may have to take away their fountain of youth.

(For more information on blood flukes and other marvels of the parasitic world, see my book Parasite Rex.)