When it comes to a study of adaptability, Alejandro Sánchez Alvarado may personify the ideal model system. Arriving at Vanderbilt University from Venezuela, he was unfazed by a lack of English skills and succeeded as an undergraduate. And when he became interested in the scientific problem of regeneration, Sánchez Alvarado was equally unfazed by the lack of a good model system. He simply succeeded in creating one.
Every day, the human body replaces an estimated 10 billion cells lost to injury or ordinary cellular housekeeping. More dramatically, salamanders, flatworms, and hydra, among other organisms, grow entirely new body parts when these are lost to injury or amputation. Scientists have marveled at such regenerative skills for centuries, but lack of good model organisms and effective techniques has managed to keep regeneration a biological mystery.
Almost single-handedly, Sánchez Alvarado has established a freshwater flatworm—an organism called Schmidtea mediterranea, or planaria—as a powerful new model system to study the molecular mechanics of regeneration. Sánchez Alvarado's lab has developed the molecular tools needed to reveal how regeneration works in this flatworm. By identifying and characterizing regeneration at the molecular level, he hopes to gain a better understanding of how higher organisms, including humans, develop biologically.
Over the past seven years, Sánchez Alvarado and colleagues have developed methods for suppressing flatworm gene function, using a technique called RNA interference (RNAi). They isolated and characterized the stem cells that underlie the flatworm's ability to regenerate, devised strategies for characterizing and sequencing thousands of relevant DNA sequences, and launched a large-scale effort to sequence S. mediterranea's genome.
Flatworms are remarkable regenerators. A fragment 1/279th the size of the original animal can regenerate a complete organism. Which genes drive this ability? To find out, Sánchez Alvarado silenced specific genes—to systematically knock out those genes expressed by S. mediterranea during regeneration. Conducting an RNAi screen of 1,065 genes in the flatworm's genome, his lab identified at least 145 genes that play pivotal roles in various aspects of regeneration. This set of genes represents previously unrecognized signaling mechanisms that specifically activate stem cells to mount a regenerative response following wounding.
In this and related studies, Sánchez Alvarado's lab has launched one of the first efforts to deconstruct the molecular and cellular components underpinning regeneration.