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Alejandro Sánchez Alvarado says that all model organisms are chosen because they exaggerate a particular biology.
All three men—Sánchez Alvarado and Newmark are now HHMI investigators, Reddien is an HHMI early career scientist—arrived at the same brilliant idea: if we want to understand how regeneration works, shouldn’t we be using the master of regeneration, the planarian? It’s a simple flatworm with rudimentary eyes, brain, gut, and gonads but no circulatory or respiratory systems. A fraction of the worm, 1/279th or just 0.3 percent, can regenerate a whole new animal. Cut off its head, a new one grows back within 10 days.
Aside from its capacity to self-renew, the planarian is a beguiling creature with its googley-eyed cartoonish look contrasted with a gliding swimming elegance. But when these researchers started, the animal had only a handful of identified genes. How to grow them optimally in the laboratory even needed work.
The scientists had all worked their way through the literature back to Thomas Hunt Morgan, who studied regeneration in planarians around the turn of the 20th century. Before he became the father of modern genetics and championed the fruit fly Drosophila melanogaster as a model organism, Morgan made a rich set of observations about the planarian’s ability to regrow itself. Through meticulous cutting and weighing, he calculated the 1/279th fraction. He also noted that if he made large cuts to amputate the head and the tail of an animal, leaving only a very thin middle section, he sometimes got a two-headed animal in its place.
Work on planarians petered out in the 1960s and 1970s as organisms more user-friendly for genetic and molecular tweaking, like the fruit fly and the roundworm Caenorhabditis elegans, took center stage.
In 1995, Sánchez Alvarado became a staff associate in the department of embryology at the Carnegie Institution for Science in Baltimore, Maryland. He made it his mission to find the best organism to study regeneration in an adult animal. The conventional thinking at the time was that regeneration was simply a recapitulation of embryonic development pathways.
That logic never sat right with Sánchez Alvarado.
“If animals are just redoing embryological developmental events, then everyone should do it. And we wouldn’t care as much about having health insurance plans,” he says. “Instead, you are asking an adult animal to form a de novo structure within an adult context.”
After reading Morgan’s 1901 book Regeneration, Sánchez Alvarado was convinced that regeneration was actually a broad phenomenon in the animal kingdom, not just an evolutionary quirk relegated to a handful of strange animals. Happy to get lost in the stacks of the Library of Congress, Sánchez Alvarado marched through the literature and found examples of regeneration in every animal phylum, from the ancient Cnidarian hydra right up to the Chordata, or vertebrate, salamander. More surprising to him were the examples in all the phyla in between.
“Almost every phylum has an example of an animal that can regenerate tissues when faced with injury and amputation,” says Sánchez Alvarado, now at the University of Utah. Even humans, after all, can regenerate significant portions of organs such as skin and liver. “Maybe the thing to do was to identify an invertebrate in which you could test hypotheses rapidly and begin ruling out what is and is not happening in regeneration,” he says. “Planarians really fit the bill.”
Photo: Ramin Rahimian