Understanding immortality, one slice at a time

Author: Guest, 05/10/16

Jovana Drinjakovic is a science writer with a background in cell and developmental biology. After completing her PhD in Cambridge (the old one) and a postdoc at the Hospital for Sick Children in Toronto, Jovana decided to switch gears and enrolled in a journalism course at the University of Toronto’s Munk School of Global Affairs. Her writing has appeared in The Globe and Mail, the National Post, The Dallas Morning News and U of T Magazine. Most days, Jovana writes about discoveries at the University of Toronto’s Donnelly Centre, where she works as a communication specialist.

An adult worm packed with neoblasts in red. Green represents differentiating epithelial cells.

An adult worm packed with neoblasts in red. Green represents differentiating epithelial cells. Credit: Bret Pearson.

An adult flatworm with its head on the left. Credit: Bret Pearson.

An adult flatworm with its head on the left. Credit: Bret Pearson.

Try as you might, it’s not easy to kill a flatworm. You can slice it up into almost 300 pieces, only to have each fragment crawl away and regrow into a fully functional worm. Or, you can zap it with radiation three times the dose that would kill a person without causing the animal any harm. As the promise of regenerative medicine grows, it is no wonder that scientists are turning to the flatworm to unlock the secrets of immortality.

One such scientist is Dr. Bret Pearson, whose group at the Hospital for Sick Children in Toronto is aiming to figure out the molecular players behind the flatworm’s unrivalled ability to regenerate. It’s their bread and butter. Each lab member has a weekly quota of worms to chop up and they are not doing this for pleasure. As the animals inevitably perish in experiments, the researchers resort to scalpels to grow more worms so they can continue their work. This means that all the worms are genetically identical – and not just in Pearson’s lab, but across the entire flatworm community – making for an easier comparison of data between groups.

At first sight, flatworms, also known as planarians, are unlikely heroes of biomedical research. About an inch long, greyish-brown, with a paper-thin body and a head dotted with two simple eyes, they are commonly found in fresh water where they prey on insects and other invertebrates. For reasons unknown, their cousins in the lab are picky eaters with a penchant for organic calf liver, which Pearson can fortunately source with ease from a nearby hipster butcher shop.

Although biologists have been intrigued by planarian regeneration for more than a century, it was not until recently that molecular and genomic technological advancements allowed researchers to begin to unpick details of this curious biology.

We now know that the planarian body is packed head-to-tail with stem cells called neoblasts that make up roughly a quarter – an astonishing amount – of cells in the adult and that are instantly recruited to injury sites for damage repair. Within a week, a tiny tail fragment will re-grow into a fully functional worm, head with eyes and a working brain included. But not all neoblasts are the same. As recent work from Dr. Peter Reddien’s group at MIT suggests, neoblasts can be separated into three classes, based on the sets of genes that are switched on. While it is not clear what the different neoblasts do, at least some of them can, when transplanted as single cells, breathe new life into a lethally irradiated worm and restore all its tissues.

But should we really care about stem cells in the flatworm, lest we feel jealous of its immortality? Having studied the planarians for more than a decade, Pearson thinks that the neoblasts can teach us something about those precious and elusive cells in our own bodies: the adult stem cells.

“How do you turn over all your tissues at different levels and still maintain your form and function throughout your life? You can use planarians as a tool to discover new pathways of adult stem cell regulation that are conserved,” says Pearson, who is also a professor in the University of Toronto’s Department of Molecular Genetics.

Adult stem cell discoveries in the last two decades have upended the previously held belief that parts of our bodies, such as the brain or heart, don’t regenerate. It has also raised hope that we might be able to mobilize these cells to treat diseases, while skirting the controversial use of stem cells from embryos.

But unlike embryonic stem cells, which are easy to isolate and grow in the lab, adult stem cells are more challenging to study. Typically tucked deep inside tissues and dividing slowly, adult stem cells are hard to find and even harder to grow. Scientists still do not fully understand how these cells communicate with their environment and so they can’t yet manipulate them to their needs. While this makes studying adult stems cells in humans extremely hard, planarian neoblasts can be tackled in a whole animal, with all the crosstalk among different cells remaining intact.

At the heart of adult stem cell biology is asymmetric cell division. When a stem cell divides, it produces an identical copy of itself and a daughter cell that goes on to create differentiated cells, such as neurons or muscle cells. This single event restores both the valuable stem cell pool and helps build new tissue.

“We are trying to find genetic markers and pathways that regulate self-renewal, and what drives non-self-renewal of the other cell. They are equally important and you can imagine that both go wrong in cancer, where both too much self-renewal and too little differentiation is bad,” says Pearson.

Not everything is smooth sailing in the planarian field. Pearson is visibly frustrated by the lack of transgenic technologies – a staple tool in other model systems – to genetically modify the worms. The challenge stems from another quirky bit of flatworm biology: No one has yet succeeded in isolating single-celled embryos, which are usually injected with DNA sequences to be inserted into the genome. The earliest detectable planarian embryo already contains thousands of cells. What happens before then is anyone’s guess, but it’s halting progress in the field. “They are totally insane,” says Pearson of the planarians, sounding like an exasperated parent of an unruly child.

But that’s precisely what’s so fascinating about them. As long as there’s enough liver to go around, the insane flatworms may be the sole simple way to study the basic biology of adult stem cells – and lessons learned could help fulfill the promise of stem cell therapy.


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