Small Fish, Big Impact
Zebrafish Give Professor Clues Into Human Disease.
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Professor Gerald B. Downes rushes into his laboratory, his mind whirring with possibilities for research that could lead to cures for diseases. “Sometimes I forget to say, ‘Hi,’” says the professor of neurobiology. “I just say, ‘Here is what we need to do.’”
Downes obviously is a man on a mission—actually several missions. With the help of a 10-member lab team and thousands of zebrafish, an ideal animal for studying neurobiology, Downes investigates neurological diseases with an eye toward finding treatments. As a professor, he wants to do more than teach biology; he wants his students to be critical and strategic thinkers. He selects undergraduates and offers them meaningful research experiences that give them an advantage in applying to medical school, graduate school, or the workforce. It is also important to him to reach out to the community to give young people an image of a scientist unlike Einstein or Doc Brown from the Back to the Future movies.
At 45, he has made quick work toward his goals. In one breakthrough, his experiments found zebrafish models that can be used to develop new treatments for maple syrup urine disease (MSUD), a rare neurometabolic disorder that can be fatal. He is establishing new animal models to study epilepsy and a disorder that combines symptoms of autism and epilepsy. Last year, he and colleagues were awarded an $824,000 grant from the National Science Foundation (NSF) to study zebrafish to better understand how the brain stem controls movement. The research uses an integrated genetic, molecular, cellular, and behavioral approach to reveal how brain stem neurons integrate sensory information and control locomotion. Basic research into cellular and molecular mechanisms of brain circuitry is essential to deeper understanding of how brains work, leading to new therapies to treat neurological disease.
Downes, the principal investigator, is working on the grant with Josef Trapani, an Amherst College neurobiologist, and James Chambers, a UMass Amherst assistant professor in the Department of Chemistry and director of the Institute of Applied Life Sciences’ microscopy facility. His innate curiosity motivates him. “I was the type of kid who would take apart an alarm clock; to me, my research is a continuation of that—taking apart something and figuring out how it works,” Downes says.
The 26,000 genes of the black and white zebrafish (Danio rerio), native to freshwater streams in Asia, offer Downes a genetic puzzle. The two-inch fish, commonly found in home aquariums, shares 70 percent of the human genetic code, while 84 percent of the genes that cause human diseases are also in zebrafish. “Nature doesn’t like to throw away a good plan,” says Downes. Besides the analogous genetics, zebrafish have other characteristics that make them superlative research specimens: They reproduce quickly, laying hundreds of eggs every two to three days. Their embryos mature outside of a womb and are transparent, allowing for easy, noninvasive study.
Downes’s fish facility, home to 2,000 to 3,000 zebrafish, is three floors below his research lab. Its steady hum provides the background track to meticulous care of the fish. The water temperature is at a constant 84 degrees Fahrenheit and water quality is continuously computer-monitored and controlled. Labels on tanks are color-coded, and feeding and cleaning carefully undertaken. When something goes awry in the lab, an alarm rings on Downes’s cell phone. He is careful and rigorous in training students and technicians who work in the fish facility. “Sloppiness begets sloppiness, and then before you know it, we have problems,” he says, “So I make sure people are doing things correctly.”
Downes is also a taskmaster—with a sweet side—in his fourth-floor research lab. He eases into Monday 8 a.m. group meetings with offerings of breads or cakes from a local bakery. The lab is neat and orderly with the requisite pipettes, beakers, centrifuges, and other equipment, as well as a shelf lined with empty bottles of champagne and sparkling cider imbibed to celebrate research landmarks or scientific papers published. His stapler is in the shape of a zebrafish; his gift to graduating students is, of course, a mug decorated with zebrafish. Microscopes hint at the lab’s critical cellular and molecular work. Researchers use these and other high-powered scopes on campus to examine embryos or young fish to learn the effects of mutations or treatment with different drugs.
True to Downes’s goals, the NSF grant includes an outreach component, with funding for him to visit science classes in middle and high schools in nearby Holyoke and Springfield. Last semester, he also organized a trip to campus for some 110 local high school students, many from disadvantaged backgrounds. “I think there is untapped potential in these communities. I also think we have a responsibility, as the flagship campus, to reach out to all kids, and these kids haven’t had the opportunity to see what we have to offer,” says Downes.
The two-inch fish, commonly found in home aquariums, shares 70 percent of the human genetic code.
His love of teaching is apparent in his work with local children and with undergraduates, who are among his biggest fans. “He expects a lot out of you,” says Meghann Zapcic ’16. “At the same time, he gives you all the tools to do the tasks he assigns.” Zapcic worked in the Downes lab for three years and took one of his courses. A graduate of Commonwealth Honors College, she majored in psychology on the neuroscience track and now attends Temple University School of Medicine. She says Downes invests in his students and creates significant research opportunities for undergraduates. “We weren’t just washing glassware and putting things into an autoclave,” she says. “We had an integral part in taking care of the fish and performing experiments.”
SO, WHY ZEBRAFISH?
The zebrafish seldom grows longer than 1.6 inches but packs tremendous power for scientific research. Its genome has been fully sequenced and it's the first vertebrate to be cloned. Zebrafish studies have produced advances in developmental biology, oncology, toxicology, reproductive studies, genetics, neurobiology, environmental sciences, stem cell research, and regenerative medicine.
Kelly Anne McKeown ’02G, ’10PhD, Downes’s first doctoral student, now teaches at Westfield State University and is on the NSF grant team. As part of the grant, two of her students joined the Downes lab for six weeks over the summer. They conducted research and attended a Downes-led weekly seminar to review published papers. Downes prods students to answer questions and explains the intricacies and conventions of science and research. For example, he explained the significance of the order of authors listed on research papers: the first author named completed the bulk of the experiments.
McKeown says her goal was to teach at a small liberal arts college and worried that Downes, who was not yet tenured and faced publish-or-perish pressures, would steer her solely into research, which would help advance his own work. On the contrary, she recalls, “He was very open to listening to me and very helpful in getting me teaching experience.”
Downes, who earned his PhD in 1999 at Washington University in St. Louis and did six years of postdoctoral research at the University of Pennsylvania, joined the University of Massachusetts Amherst faculty in 2005. Massachusetts is his home state and UMass Amherst is the alma mater of his father, Stephen F. Downes, who earned a graduate degree in engineering in 1981. He says he and his wife, Kimball Prentiss (a pediatric emergency medicine physician at Baystate Medical Center in Springfield and a 2002 graduate of UMass Medical School), enjoy Amherst with its easy access to nature. But with a three-year-old son and infant daughter, Downes’s time for snowboarding, hiking, and cycling are limited.
When he completed his postdoctoral work on mutant zebrafish genes that control swimming, he spurned the idea of working at a private university. He explains: “I wanted to do something for the greater good, and public service and public universities are a noble calling.”
Working at UMass, with the support of the NSF, his students, and colleagues, along with the big contributions of many small fish, Downes and his research hold the promise of help for people with debilitating neurological problems.