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Earning their stripes
Animals have long had their place in drug discovery. Mice, rats, fruit flies and primates all serve as test platforms and analogs for potential drug candidates given the similarities we share biologically. But there's one rather unusual species that been gaining interest in recent years: zebrafish.
The interest in zebrafish might seem out of place, but they have a lot going for them. These fish are extremely resilient, and reproduce rapidly: an embryo matures into a developed fish within about 24 hours, much less than the roughly three weeks required for mouse gestation. And since the embryos are transparent, researchers can directly observe the results of altering gene functions via microscopes.
Some of the recent work with these fish is taking place at the University of California, San Francisco (UCSF), where researchers have found that tests with zebrafish indicate that an antihistamine commonly used to treat itching might be capable of preventing seizures in children suffering from Dravet syndrome, a rare genetic disorder that results in dozens of daily seizures and significant cognitive and social deficits.
This avenue of research began when Dr. Scott C. Baraban, the UCSF William K. Bowes Jr. Endowed Chair in Neuroscience Research and professor of neurological surgery, and his team discovered zebrafish that presented with a genetic mutation identical to the one that causes Dravet syndrome.
"We believe our approach could have tremendous impact on how we identify new drug candidates for all forms of monogenic epilepsies, and perhaps other neurological diseases," says Baraban. "Basically, any epilepsy that is associated with a single gene mutation can be modeled in zebrafish and then used in the phenotype-based high-throughput screen we have pioneered. Because zebrafish are intact vertebrates they have an added advantage of assessing toxicity at the same time, a major problem when moving lead compounds from the bench to the clinic. Zebrafish larvae offer a significant advancement over cell-based assays where whole-animal toxicity cannot be evaluated during the drug discovery process."
Seeing as how one pair of adult zebrafish can produce several hundred larvae, Baraban notes that "even with a very modest mating schedule it is very easy to screen 20 to 50 drugs per month." In addition, "the zebrafish genome is approximately 70 percent identical to humans, and when one considers only disease-based genes, this number is over 80 percent." Baraban adds that it is also fairly easy to generate zebrafish models of human genetic disorders.
A few hundred miles east of UCSF, another team is examining zebrafish in hopes of finding a way to cure deafness. Bruce Riley, a biology professor at Texas A&M University, is taking advantage of the genetic similarities between humans and zebrafish to study the latter's inner-ear development.
Zebrafish are among the types of fish considered hearing specialists, according to Riley. They are able to regenerate hearing, an ability shared by most vertebrates but that humans and all mammals have lost. If a mature zebrafish hair cell is damaged by researchers with a laser, the fish's regeneration response can restore that cell within 12 to 24 hours by reactivating early developmental genetic programs. In humans, if a hair cell dies, it's gone for good. If the mechanism for controlling this regeneration can be identified, it could shed light on how to recreate that process in humans.
In 2010, Riley published a paper detailing that the disruption of a gene called SOX2 in zebrafish prevents the regeneration of a destroyed hair cell. That gene is also found in the human ear, but after birth, the amount of expression of SOX2 is significantly reduced. Riley believes our inability to regenerate lost hair cells is due to a paucity of SOX2.
"Our research is founded on the simple idea that the genes that control the development of the inner ear are the same in fish and humans. We're trying to figure out what genes control regeneration of zebrafish hair cells, which control hearing. The hope is that if we can understand them, maybe we can figure out a way to coax a similar response out of the equivalent cells in a human. I absolutely believe that's going to happen in our lifetime. And in principle, it could literally be a cure for deafness," said Riley.