Wed 15 Jul 2015
By Kelsey Calhoun
The most exciting phrase to hear in science, the one that heralds new discoveries, is not “Eureka” but “That’s funny…”
—Isaac Asimov (1920–1992)
The process of science is rarely predictable: there are some 180s, some hard left turns, and quite a few long and winding roads. Graduate student Drew Friedmann can attest to this fact: a year and a half ago he was pursuing a completely different research topic and getting nowhere. But it was at the end of some long and frustrating months that he uttered some of the most exciting words you can hear from a scientist: “That’s funny,” or more specifically in this case, “Zebrafish don’t see with their tails.”
Friedmann, a 2015 Grass Fellow at the MBL, had originally set out to study what controls the movement of zebrafish. These two-inch-long fish are widely studied, partly because they are transparent when young, making it easy to track their development. Ehud Isacoff’s lab at University of California-Berkeley, where Friedmann is a graduate student, has mapped the flow of calcium—a proxy for neuronal activity—in the nerve cells of developing zebrafish as they move.
Taking this further, Friedmann hoped to focus on how these young fish manage to move by looking at their gap junctions, the direct connections between cells which help them talk to one other. But there are over 30 different types of building blocks, called connexins, that make up these gap junctions, and few clues as to which ones help control movement as the zebrafish develop. Friedmann spent a long, frustrating year tackling this question with different tools and methods, without getting many interesting results.
One day, he tried genetics. Analyzing only the neurons controlling movement in zebrafish tails—the most motile part of the fish—yielded a long list of active genes. One gene on the list, VALopA, caught Friedmann’s eye, because it codes for an opsin, a light-sensitive protein usually only found in eyes. “I went, what is that doing here?” Friedmann remembered. “There are no eyes in the sample!”
The “that’s funny” moment seemed odd enough to merit a little digging. “I’ll just flash some lights and see what happens,” Friedmann thought. The Isacoff lab uses a plethora of microscopes to track the flow of calcium around zebrafish, including a bright green laser. “I was expecting to flash the laser and see a calcium event,” Friedmann explained. But no such luck—light was not stimulating the neurons, embedded with light-sensitive proteins, to fire. Frustrated, Friedmann tried for a while longer, and finally noticed something else odd. If these neurons really didn’t respond to light at all, there should have been a random calcium spike or two right after a light flash, but there wasn’t. There was never a spike after a light flash; instead, the light was actually inhibiting the neurons from firing.
This presents a whole new unexpected puzzle: Why are light-sensitive, movement-controlling neurons inhibited by light? “This opens up two, maybe three big questions,” Friedmann says. “One is how, one is why, and one is how common is this?” Zebrafish always lay their eggs at sunrise, so their development may be affected by light and movement, making it evolutionarily advantageous for the two to be linked. Friedmann’s goal this summer at MBL is to figure out what other cells and systems these light-sensitive neurons are connected to, and trace the full circuit involved in light response. He’s supported at the MBL by a Grass Foundation fellowship, which are given to early-career scientists to carry out independent, investigator-designed projects. The Grass Lab at MBL provides space, cutting-edge equipment, supplies, and housing, so young scientists can spend a summer dedicated to experimentation.
The ability to detect light evolved before eyes, Friedmann explains, and when eyes did evolve, there was no reason to get rid of the old way of sensing light, especially for transparent creatures like zebrafish. These light-sensitive neurons may be heavily involved in healthy zebrafish development and behavior, paving Friedmann’s winding road with all sorts of interesting questions.