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Download PDF of This Story MASTER OF REGENERATION ¤ by Kendall Powell Once a high school biology oddity, planarians illustration by Jason Holley are moving into the spotlight to reveal secrets of self-renewal. As the plane touched down in Barcelona on a Saturday afternoon in September 1998, Alejandro Sánchez Alvarado was excited to see the runway pavement slick from a recent rainfall. Rain would have filled up the abandoned fountains in Parc de Montjuïc where he and Phil Newmark hoped to trap their quarry. » August 2o1o | HHMI BULLETIN 29 works, shouldn’t we be using the master of The conventional thinking at the time was THE TWO regeneration, the planarian? It’s a simple that regeneration was simply a recapitula- flatworm with rudimentary eyes, brain, tion of embryonic development pathways. HURRIED gut, and gonads but no circulatory or respi- That logic never sat right with Sánchez ratory systems. A fraction of the worm, Alvarado. IN A CAB 1/279th or just 0.3 percent, can regenerate “If animals are just redoing embryolog- TO THE a whole new animal. Cut off its head, a ical developmental events, then everyone new one grows back within 10 days. should do it. And we wouldn’t care as NEAREST Aside from its capacity to self-renew, much about having health insurance the planarian is a beguiling creature with plans,” he says. “Instead, you are asking an BUTCHER its googley-eyed cartoonish look con- adult animal to form a de novo structure trasted with a gliding swimming elegance. within an adult context.” FOR A SLAB But when these researchers started, the After reading Morgan’s 1901 book animal had only a handful of identified Regeneration, Sánchez Alvarado was OF SHEEP’S genes. How to grow them optimally in the convinced that regeneration was actu- laboratory even needed work. ally a broad phenomenon in the animal LIVER, kingdom, not just an evolutionary quirk their target’s preferred dinner, and then REGENERATION REVIVAL relegated to a handful of strange animals. went straight to their hotel room to fashion The scientists had all worked their way Happy to get lost in the stacks of the traps by stuffing the liver bait into empty through the literature back to Thomas Library of Congress, Sánchez Alvarado bottles. They needed to set the traps in Hunt Morgan, who studied regeneration marched through the literature and found half a dozen of the park’s fountains before in planarians around the turn of the 20th examples of regeneration in every animal nightfall. They had only a long weekend century. Before he became the father of phylum, from the ancient Cnidarian hydra and they were taking a big gamble that modern genetics and championed the right up to the Chordata, or vertebrate, their traps would lure swarms of what they fruit fly Drosophila melanogaster as a salamander. More surprising to him were hoped would be developmental biology’s model organism, Morgan made a rich set the examples in all the phyla in between. next important model organism: the pla- of observations about the planarian’s abil- “Almost every phylum has an example narian flatworm, Schmidtea mediterranea. ity to regrow itself. Through meticulous of an animal that can regenerate tissues Transforming the planarian worm cutting and weighing, he calculated the when faced with injury and amputa- from a fountain-dwelling, biology class- 1/279th fraction. He also noted that if he tion,” says Sánchez Alvarado, now at the room novelty—cut one in quarters, get made large cuts to amputate the head and University of Utah. Even humans, after four worms—to a workhorse of molecular the tail of an animal, leaving only a very all, can regenerate significant portions of developmental biology was an adventure thin middle section, he sometimes got a organs such as skin and liver. “Maybe the both inside and outside the laboratory. two-headed animal in its place. thing to do was to identify an invertebrate The quest took Newmark and Sánchez Work on planarians petered out in the in which you could test hypotheses rap- Alvarado—and later Peter Reddien—to art 1960s and 1970s as organisms more user- idly and begin ruling out what is and is stores, to amputation assembly lines, and friendly for genetic and molecular tweaking, not happening in regeneration,” he says. into the genome that controls one of the like the fruit fly and the roundworm Cae- “ Planarians really fit the bill.” most robust abilities to regrow body parts norhabditis elegans, took center stage. anywhere in the animal kingdom. In 1995, Sánchez Alvarado became a A CHANCE MEETING All three men—Sánchez Alvarado and staff associate in the department of em- Amid antique locomotive engines at Newmark are now HHMI investigators, bryology at the Carnegie Institution for the National Railway Museum in York, Reddien is an HHMI early career scien- Science in Baltimore, Maryland. He made England, Sánchez Alvarado sat next to tist—arrived at the same brilliant idea: if it his mission to find the best organism to Newmark at the 1996 annual meeting we want to understand how regeneration study regeneration in an adult animal. banquet of the British Society for Devel- 30 HHMI BULLETIN | August 2o1o Below: Alejandro Sánchez Alvarado says that all model organisms are chosen because they exaggerate a particular biology. opmental Biology. At the time, Newmark Newmark. “There were plenty of people stem cells—which are called neoblasts was in Jaume Baguñà’s lab at University [along the way] who thought this was and make up roughly 30 percent of the of Barcelona as a Damon Runyon Cancer craziness.” animal’s cells—the team had to work Research Foundation postdoctoral fellow, The two personified dogged persis- through trial and error. They figured out learning everything he could about funda- tence. Early on, they spent a sleepless how to label the neoblasts and began mak- mental planarian biology to eventually set weekend cutting heads and tails off of ing libraries of the genes expressed during up a line of research in the United States. about 1,000 animals. These experiments various stages of regeneration. “Here I found another member of my would tell them in the coming months During his time at Carnegie, New- tribe,” recalls Sánchez Alvarado. The two which genes were expressed in intact mark also created a genetically identical contemporaries, just one year apart in heads and tails compared with regen- line of worms by cutting and growing up age, hatched a plan to convince the Carn- erating heads and tails. Newmark also pieces from one individual collected from egie Institution and Damon Runyon to worked on modifying an in situ hybrid- the Barcelona park. That line has been let Newmark be a postdoc with Sánchez ization protocol, which is used to mark going for almost 12 years and is used by all Alvarado. The two would attempt to turn specific genes with a dye to see where the the planarian laboratories in the United planarians into a cultured lab animal that gene is turned on in the whole animal. It States. No more mucking through dor- could serve as a system for deconstruct- wasn’t easy. The animals’ mucus covering mant fountains. ing the molecular pathways that control tended to suck up the dye and turn every- In 1998, Andrew Fire, working down- regeneration. thing dark blue. stairs from the two at Carnegie, had Both Carnegie and Damon Runyon With almost any method they discovered a way to silence specific genes “really took a risk and supported us,” says attempted for tracking the planarians’ in C. elegans. The method, called RNA Ramin Rahimian August 2o1o | HHMI BULLETIN 31 Below: Along with Sánchez Alvarado, Phil Newmark (left) and Peter Reddien brought planarians into the molecular era. interference, or RNAi, works by introduc- Now they had a loss-of-function assay LEARNING CURVE ing a double-stranded RNA that matches for the planarians—a tool with which Reddien discovered Morgan’s work during the message of the gene a researcher to ask, if this gene is missing, how does his graduate studies. That quickly led him wants to knock down. The RNAi sets it affect the regeneration mechanism? to Sánchez Alvarado and Newmark’s 1999 off a process in the cell that destroys All they needed was some regeneration- Proceedings of the National Academy of the mRNA message. The method, for specific genes to test. Sciences paper on the RNAi work. which Fire shared the 2006 Nobel Prize “We needed to clone genes like there “The things they had shown gave in Physiology or Medicine with HHMI was no tomorrow so that we could do me hope that turning planarians into a investigator Craig Mello, effectively turns RNAi screening. That kept us occu- molecular model organism would work,” off the gene. pied for eight years or so,” says Sánchez Reddien recalls. “They were bold with Fire asked Newmark and Sánchez Alvarado. Newmark calls the RNAi work their choices and had taken a massive risk.” Alvarado to try RNAi in planarians to see if a crucial breakthrough from their years at Reddien joined Sánchez Alvarado as the method would work beyond C. elegans. Carnegie: 1997 to 2001. a postdoc at the Utah laboratory and his Sánchez Alvarado first tried silencing the “Now we could do functional biol- first task was to use RNAi for a large screen planarian tubulin and myosin genes since ogy. We could ask whether inhibiting the of planarian genes. It was still unclear if the resulting proteins are found in every expression of a given gene could disrupt this approach could silence genes well cell and he had the dyes to track them.
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