ALEX SCHIER'S ZEBRAFISH OFFER VIEW INTO DEVELOPMENT AND BEHAVIOR
December 13th, 2005
Pet stores recommend zebrafish as a child’s first fish because they’re hardy (but for their aversion to chlorinated tap water). Similarly, a pet store recommended these tiny, striped fish to George Streisinger, often considered the founding father of zebrafish research, who, in the late 1970s, was trawling for a pliable but robust model organism for studying development and behavior in vertebrates.
"Zebrafish are great," Schier says. In 48 hours, they go from fertilization to the end of embryogenesis. "They’re transparent as embryos, so you can see every cell and inside every cell. You can combine embryology with genetics to find mutations that affect development. You can observe at the subcellular level what a gene is doing."
Schier had no inkling that fish would catapult his career from his native Basel, Switzerland, to Harvard University. True, he had a painting of a fish over his bed as a child, but that reflected more on his long-standing artistic and cultural interests.
Schier undertook doctoral studies with the renowned Walter Gehring in Basel, Switzerland. "He was one of the first to combine genetics with molecular biology in order to understand developmental biology. It was a very exciting time," Schier recalls. "His research group found some of the first genes that control development." They were the homeobox genes, a cassette of genes that researchers now realize are remarkably conserved from simple invertebrates to humans.
That research, though, focused on the fruit fly Drosophila, an invertebrate. For his postdoctoral work, Schier wanted to study the genetics of vertebrate development, and that led him to work on zebrafish at Massachusetts General Hospital, a Harvard-affiliated hospital.
"We performed a big screen for mutant genes that affect zebrafish development," Schier says, which had never been done in vertebrates. "Two years later, we had hundreds of mutant fish for various aspects of animal development. A whole new world opened up," and the work filled an entire issue of the journal Development in 1996. The different phenotypes of the fish provided entry points into many different processes in development and beyond, from how the brain, heart, and blood develop to behavior, such as how embryos swim away when touched. Ten years later, research groups around the globe still focus on this collection of mutant fish. In 1996, Schier accepted the invitation to join the brand new Skirball Institute of Biomolecular Medicine, founded to boost basic research at New York University’s School of Medicine. "We had an entire floor for developmental genetics," he remarks.
There, Schier focused on what genes give rise to the different mutant phenotypes, and then he cloned the genes to study their molecular defects. Suppose one mutant zebrafish is missing a part of its brain. Discovering the missing or defective gene pinpoints a key gene required for building the brain. One of Schier’s favorite discoveries was the one-eyed pinhead mutant. This cyclopic fish turned out to have a gene whose function was not yet known. He found it fit into the nodal signaling pathway, which plays important roles in development and also in the generation of tumors and birth defects.
"This was an important proof of principle that we could use these screens to identify a gene not previously defined," he comments. "It also gave us the tools to study the mechanism for how these molecules interact and how the signaling pathways regulate gene expression, cell movement, and so on. That’s the power of the approach."
For the past 10 years, Schier has used this method to study "one of the most fascinating problems in biology," how a fertilized egg transforms into an embryo. At one of the earliest stages, called gastulation, the unstructured sheet of embryonic cells becomes layered into the ectoderm (which will eventually become organs like the skin), mesoderm (heart, kidney, blood), and endoderm (gut, pancreas, liver).
Molecular signals in the nodal pathway control this sudden increase in complexity as the embryonic cells commit to becoming different tissues and migrate to the proper places. Schier has described how a signal that is produced locally can influence cells at a distance. As the signal’s concentration changes, so too does its effect on a cell’s decision to become a specific type of tissue. "This was an old concept," he explains, "but had not been clearly shown in vertebrates."
|Alex Schier Wins Two Awards
McKnight Neuroscience of Brain Disorders Award
H.W. Mossman Developmental Biologist Award
Alex Schier was awarded the 2006 Harland Winfield Mossman Developmental Biologist Award of the American Association of Anatomists. He will present an award lecture entitled "The Molecular Genetics of Zebrafish Embryogenesis: From Nodal Signals to Micro RNAs," at the American Association of Anatomists’ (AAA) annual meeting. The H.W. Mossman Award is presented annually "to recognize young investigators who have made important contributions to the field of developmental biology and have demonstrated remarkable promise of future accomplishments."
AAA Press Release [doc file]
Going deeper, Schier also looks at how a signal travels from the cell where it is made to the cells that respond, and how a cell receives the signal and then transmits it to the genes that will respond with varying activities. "With the zebrafish embryo, we can observe these processes in a living animal because it’s transparent. We can use high resolution imaging and look at the molecules and cells," says Schier.
In the past few years, Schier has also been researching neurobiology by studying how sensory neurons for heat and other stimuli develop—and function to keep animals away from danger. His group is analyzing how neurons group together to form a nerve center and how nerve cells innervate the skin.
In the September 2005 issue of Neuron, Schier showed that chemokine signals, which are known to attract immune cells, also attract neurons that are born in separate places to come together to form a nerve center. "It’s a parallel story to the nodal signals," he comments. "Nodal signals influence cells to affect their fates. The chemokines act to affect cell movement."
To avoid harmful stimuli, a zebrafish depends on its senses of touch and temperature, which tell it when to swim away. For this, it needs neuron coverage over the entire area of its skin. How do the touch neurons manage to innervate the entire area without overlap or leaving blind spots? The answer, Schier has found, lies in repulsive signals among the axons. "They grow where no one else is," he says, "and when they meet someone else, they are repelled and stop growing in that direction."
Ever inquiring, Schier now wants to know how these touch neurons connect to the rest of the nervous system, and how they elicit behavior. "What is the connection from a touch on the skin to contracting the muscles to swimming away?" he asks.
Schier has also begun tinkering with another age-old mystery—why animals sleep and what cellular signals tell them to do so—by studying the genes and neural circuits of zebrafish that sleep more or less than the usual 10-hour downtime in the tank.
Since joining the Department of Molecular and Cellular Biology at Harvard in September, Schier has been setting up his lab with the six postdoctoral researchers and five graduate students who accompanied him from New York. His teaching responsibilities will include developmental biology and lab courses.
"Alex has been one of the leading researchers to use the genetics of a simple model system to understand how our own tissues form and are shaped, and he will complement MCB’s existing strengths in developmental and cellular biology," says Professor Andrew McMahon, MCB’s Frank B. Baird, Jr., Professor of Science. "This research will synergize with MCB’s systems neuroscience as well as the FAS-wide initiative in Brain Sciences.
"The interactions with MCB faculty have already changed my way of thinking about problems," says Schier, thanks in part to the joint meetings with other labs. "I like the opportunity to approach a problem from many different angles. We can ask someone in systems biology or engineering for new ways to tackle basic questions in biology."
For now, Schier is sticking with zebrafish. But down the road, he says, "We might want to find out what the equivalent of a zebrafish gene is doing in mammals. Or, for systems biology questions, we might move to a simpler model, like the fruit fly, and see how our favorite genes fit into complex networks."