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Tuesday, June 6, 2023

Glowing Worms Could Shed Light On the Secrets of Regeneration

In 1961, Osamu Shimomura and Frank Johnson isolated a protein from jellyfish that glow green under UV light. Corals, too, can fluoresce in a wide range of hues, thanks to similar proteins. Now scientists at Harvard University have genetically modified the three-banded panther worm to enable the creature to emit a similar green glow, according to a new paper published in the journal Developmental Cell. Their hope is to uncover the secrets to regeneration.

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Most animals exhibit some form of regeneration: regrowing hair, for instance, or knitting a fractured bone back together. But some creatures are capable of particularly amazing regenerative feats, and studying the mechanisms by which they accomplish these could have important implications for human aging. If a salamander loses a leg, the limb will grow back, for example, while some geckos can detach their tails as a distraction to evade predators and then regrow them later. The zebra fish can regrow a lost or damaged fin, as well as repairing a damaged heart, retina, pancreas, brain, or spinal cord. Cut a planarian flatworm, a jellyfish, or a sea anemone in half, and it will regenerate its entire body.

And then there is the three-banded panther worm (Hofstenia miamia), a tiny creature that looks a bit like a plump grain of rice, so named because of its trademark trio of cream-colored stripes across its body. If a panther worm is cut into three parts, each part will generate into a fully formed worm within eight weeks or so. These worms are found primarily in the Caribbean, Bahamas, and Bermuda, as well as Japan, and they are voracious predators, not above taking a few bites out of their fellow panther worms if they're hungry enough and can't find other prey. They also offer a promising new model for studying the mechanics of regeneration.

Coauthor Mansi Srivastava, an evolutionary biologist at Harvard University, has been studying the three-banded panther worm since 2010, when she was a postdoc scholar in Peter Reddien's lab at MIT's Whitehead Institute. They collected 120 or so of the worms in Bermuda and brought them back to Cambridge. The worms did not immediately adapt to laboratory life: Srivastava and Reddien had to figure out the correct salinity levels for their water and find an acceptable food source. The worms didn't care for the liver Reddien had been feeding his planarian flatworms, and a few resorted to cannibalism to survive. Eventually, the researchers figured out that the panther worms loved brine shrimp (aka sea monkeys), and the creatures finally began to thrive and breed.

A report in 1960 had claimed that the worms could regrow their severed heads, but there was little scientific follow-up. Reddien and Srivastava's early experiments proved that the panther worms could not only regrow their heads, they could regenerate pretty much any body part, just like the planarian flatworms—even though the two are only distantly related. Srivastava now runs her own laboratory at Harvard studying regeneration in panther worms.

In 2019, Srivastava and her lab released the full genome sequence of the panther worm, as well as their identification of a number of "DNA switches" that appear to control the genes for whole-body regeneration. Specifically, they pinpointed a section of noncoding DNA that controls whether a kind of "master control gene" for regeneration, known as early growth response (EGR), is activated. EGR can, in turn, switch other genes involved in various processes on or off. If EGR isn't activated, regeneration in the worms can't occur.

EGR is also present in other species, including humans—and yet humans cannot regenerate their entire bodies. According to Srivastava, the process likely works very differently in humans than in the panther worms. "If EGR is the power switch, we think the wiring is different," she told The Harvard Gazette at the time. "What EGR is talking to in human cells may be different." Discovering more about how the genome interacts on a larger scale, rather than just at the level of individual switches, will be key to future breakthroughs. In other words, it's not just which genes are present, but how they are wired or networked together that enables full-body regeneration.

For this latest study, Srivastava and her colleagues figured out how to breed transgenic panther worms by introducing a gene that encodes a fluorescent protein. There are various kinds of fluorescent proteins, the most famous of which is green fluorescent protein (GFP).

GFP contains a special chromophore that absorbs and emits light. Shining UV or blue light on the chromophore causes it to absorb the energy, become excited, and then emit the excess energy as green light. GFP has since become a standard tagging tool for researchers all over the globe, enabling them to study biological processes previously invisible to the naked eye at the cellular level.

Srivastava and her team injected DNA modified to express a fluorescent protein into just-fertilized panther worm embryos, which were then incorporated into the genomes of other cells as they divided, again and again, until the embryos became full-grown worms. The adult worm's muscle cells glow green under UV light, and that fluorescent ability will be passed down to the worm's offspring. "We don't know how any one of these cells actually behave in the animal during regeneration," said Srivastava. "Having the transgenic worms will allow us to watch the cells in the context of the animal as it regenerates."

Thus far, this window into the inner workings of the panther worms as they regenerate has yielded structural insight into how the creatures' muscle fibers connect to each other, as well as to other cells. Srivastava et al. reported that extensions on the muscle cells interlock in columns to create a tight-knit grid, akin to a skeleton. The next step is to determine whether the muscles only serve a structural purpose or are involved in storing or communicating information about the regeneration process.

This article originally appeared on Ars Technica. 

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