Peering into a tiny living animal, I watch the motion of its beating heart and see hundreds of individual blood cells march through its arteries. The skin of the zebrafish is transparent for its first few days of life, beginning with its development in a clear egg, so the egg can be placed under a microscope, and the growth of the entire nervous system can be viewed in real time. I can see directly into the growing brain, which, amazingly, only takes about 40 hours to fully develop. This observation is not possible in any other animal, and it makes the zebrafish a powerful tool for studying development and disease.
Scientists use these unique critters to probe a plethora of previously unanswered questions. In my research laboratory at Lewis & Clark College, for example, we watch the very cells that are affected by the mosquito-borne Zika virus, which tragically causes microcephaly—in which the head and, typically, brain are significantly smaller than normal— in newborn babies. The stem cells in an embryo’s nervous system are busy dividing over and over again to produce all of the neurons needed for the growing organism. If those cells are infected by the virus, however, they don’t make enough neurons, and the brain will remain underdeveloped.
We use a tool called Brainbow to label the stem cells with different colors and watch them divide inside the living zebrafish. Beyond generating beautiful images that have been featured previously by Scientific American, Scientific American Mind and other outlets, the multicolor Brainbow technique illuminates many dividing cells all at once. Now able to clearly track cells nestled deep inside the brain, we can pursue specific questions about how and when the cells divide and die.
The zebrafish, native to South Asia and first harnessed for modern scientific use in the 1970s, is now also helping us to understand the brain’s complex response to the visual world. For the first time, scientists are able to observe and record the firing of every single neuron in an entire brain, allowing us to watch how a whole circuit of nerve cells responds to stimuli. Fish are placed in a recording chamber, where they view different shapes that mimic approaching predators or other objects. As they respond to each stimulus, a computer tracks the electrical activity in their brain.
Precisely how the brain generates behaviors like these is still largely a mystery. From work in zebrafish, we are beginning to piece together a functional map that was impossible to see before using this type of holistic imaging technique. That map, in turn, informs us about how the neural circuits in our own brain may be organized and how we generate our own behaviors.
Surprisingly, zebrafish research can also help us to understand human deafness. Along the outer edge of the fish, there is a specialized organ used for detecting movements in the water. This sensory system, called the lateral line, uses delicate “hair cells” that are very similar to the ones found in our own ears. In humans, these cells sense pressure waves in the air, sending signals to our brain that represent sound.
We know that those cells can become damaged over time, leading to age-related and other kinds of hearing loss. In fish, these same hair cells are activated when nearby objects cause movements in the water. Researchers can model hair-cell loss in fish by damaging them with a particular drug and then testing their ability to regenerate. Using zebrafish, researchers have learned about the specialized stem cells and genes that are required for this critical process—insights that may pay off some day in efforts to restore hearing in humans.
The fish are also a powerful model for studying numerous genetic diseases. The precise mutations that arise in humans can be mimicked in a zebrafish, while the affected cells are followed in real time under the microscope. Drug treatments that may eventually cure human diseases such as cancer are then added to the fish’s water to test how the cells respond inside the animal.
Though small, the transparent zebrafish is making important contributions to our understanding of human biology. Beyond its direct impact on medicine, the fish inspires young people across the globe. The model organism is used in elementary schools and college classrooms to demonstrate the wonder of embryonic development. In my own lab, I have witnessed a powerful impact on students when they look directly into the zebrafish brain for the first time. It opens a window of curiosity that can inspire undergraduate scientists, who will ultimately develop new approaches and become the next generation of cutting-edge researchers