The homepage of Alejandro Sánchez Alvarado’s lab at the Stowers Institute for Medical Research depicts a glowing image of the flatworm planaria packed with stem cells, next to a list of lab “headlines”— the names of students who had gotten their PhDs, a greeting to a new lab technician, and news that a post-doc just landed a great job in Europe.
After decapitation and tail amputation, planarians regenerate the missing body parts in about a week (top). If the Hedgehog pathway is silenced by RNAi, then no tails are formed (middle). In contrast, if the pathway is overactivated, then tails regenerate at both ends (bottom). Green: gut; Red: central nervous system; Blue: cell nuclei.
Image: Sanchez lab.
A celebration of labworkers’ personal landmarks is rare on most lab websites, or at best a few clicks away. Small wonder that when Sánchez Alvarado recently re-located to Stowers to continue work on that regenerative marvel, the planaria Schmidtea mediterranea, so did most of his lab. That may be because people’s stories, be they students, colleagues or historical figures, are completely inseparable from Sánchez Alvarado’s lifelong attempt to “understand the origin of things.”
Sánchez Alvarado’s research centers on regeneration, and as a model system he uses Schmidtea, which when halved or quartered (even by high school students) can clone itself from the pieces. That remarkable feat was first recognized over 100 years ago by geneticist Thomas Hunt Morgan.
As astonishing as this is, Sánchez Alvarado thinks we all have a bit of “planaria” hidden in our genomes. “You and I are turning over a number of cells equivalent to our body weight every year,” he says. “I lost billions of cells yesterday but this morning I still recognized myself in the mirror. That’s because basic mechanisms are in place to retain our original form and function.”
In relocating to Stowers, Sánchez Alvarado moved his entire planaria colony from Utah. “Stowers provided what I think is the first planarian core facility on the planet,” he said, explaining that once a few planaria “scouts”—sent to Stowers via FedEx—survived in the new tanks, thousands more followed. “Things have gone swimmingly.”
Swimmingly, because water is where Schmidtea lives in the real world. “Legend” has it that in 1998 when after Sánchez Alvarado and fellow planarian biologist Phil Newmark decided that Schmidtea was the model of choice to take apart regeneration molecularly, they flew to Barcelona to catch worms in a fountain using liver-baited traps.
p53 is primarily expressed in the non-dividing progeny of planarian stem cells. Whole mount in situ gene expression visualization shows cells expressing p53 (green) and the stem cell marker piwi (left panel); early division progeny (middle panel) and late division progeny (right panel). The overlap in expression is most obvious in the middle panel.
Image: Sanchez lab.
Since then, from his Staff Associate position at Baltimore’s Carnegie Institution for Science through his faculty position at the University of Utah’s School of Medicine, Sánchez Alvarado’s lab has produced a series of mechanistic studies moving planaria from the status of biological oddball to a genetically tractable organism.
In 1998, for example, prompted in great part by the insistence of his downstairs neighbor at Carnegie, Andrew Fire, who won the Nobel Prize for devising RNA-mediated genetic interference (RNAi) in C. elegans, Sánchez Alvarado tested this method in planarians and reported its efficiency and robustness in 1999 in an article published in the Proceedings of the National Academy of Sciences. This work paved the way for the first planaria RNAi gene-silencing screen for regeneration-related genes, published in 2005 in Developmental Cell.
Sánchez Alvarado then employed that technology to show how planaria know their heads from their tails—valuable information if one plans to regenerate one from the other. That study, published in 2008 in Science, reported that worms know anterior from posterior similarly to the way we do—through so called Wnt signaling.
And in another study published in a 2008 Cell Stem Cell article, his lab reported a molecular screen for genes expressed in planaria’s multitudinous adult stem cells, or neoblasts. Many of those genes encoded worm versions of vertebrate chromatin-associated factors, supporting the idea that regenerative capacity requires the ability to remodel chromatin.
Animated 3D projection of the planarian kidney units (protonephridia) showing inx10 in red, CAVII-1 in green and tubulin in blue.
Video: Courtesy of Dr. Jochen C. Rink, MPI of Molecular Cell Biology and Genetics, Dresden, and Hanh Thi-Kim Vu, Sanchez lab.
From there, some investigators might be tempted to dive headlong into stem cell minutiae. But Sánchez Alvarado feels that biologists must stay focused on the organism and the biology that prompted its selection as a model system. “We need to keep in mind where these cells live—outside a Petri dish,” he says. “If we become too highly specialized in our research interests, then we’re no better than insects.”
Far from narrowly-focused, Sánchez Alvarado is an unapologetic multi-tasker. He maintains his own private mini-lab with a couple of microscopes right outside his office door so he can take videos of new worm strains and work at his desk at the same time. He also maintains an extremely demanding travel schedule, lecturing and teaching worldwide.
“At meetings abroad, I love to sit down and have coffee with new colleagues and talk science in English with our respectively colorful accents,” says Sánchez Alvarado, who grew up in Venezuela. “People before us were not presented with these trans- and inter-continental face-to-face opportunities as frequently as we are today.”
Sánchez Alvarado is renowned in his field for his knowledge and appreciation of the history of science, as evidenced by a 2008 Cell commentary he wrote about a biography of biologist Ernst Haeckel. Historical personages are not abstractions to Sánchez Alvarado: he mixes conversation about how to stop grad students from mooching his solutions with reflections about what Thomas Jefferson or Louis Pasteur were thinking, as if he just got off the phone with them.
Among books that shaped his thinking, Sánchez Alvarado cites Paul de Kruif’s “The Microbe Hunters,” which he read in Spanish in high school, as particularly intriguing. That collection of biographies of giants of microbial biology has inspired his life-long fascination with the human side of discovery.
“Van Leeuwenhoek didn’t just refine the microscope and invent modern microscopy—he also had toothaches!” he says. “These guys had no idea that years later some guy from Caracas working in Kansas City would be reading their stories and thinking about their work and life—their ideas still resonate.”