Earning their stripes

Zebrafish continue to gain popularity as lab models for drug discovery

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Animals have long had their place in drug discovery. Mice,rats, fruit flies and primates all serve as test platforms and analogs forpotential drug candidates given the similarities we share biologically. Butthere's one rather unusual species that been gaining interest in recent years:zebrafish.
The interest in zebrafish might seem out of place, but theyhave a lot going for them. These fish are extremely resilient, and reproducerapidly: an embryo matures into a developed fish within about 24 hours, muchless than the roughly three weeks required for mouse gestation. And since theembryos are transparent, researchers can directly observe the results ofaltering gene functions via microscopes.
Some of the recent work with these fish is taking place atthe University of California, San Francisco (UCSF), where researchers havefound that tests with zebrafish indicate that an antihistamine commonly used totreat itching might be capable of preventing seizures in children sufferingfrom Dravet syndrome, a rare genetic disorder that results in dozens of dailyseizures and significant cognitive and social deficits.
This avenue of research began when Dr. Scott C. Baraban, theUCSF William K. Bowes Jr. Endowed Chair in Neuroscience Research and professorof neurological surgery, and his team discovered zebrafish that presented witha genetic mutation identical to the one that causes Dravet syndrome.
"We believe our approach could have tremendous impact on howwe identify new drug candidates for all forms of monogenic epilepsies, andperhaps other neurological diseases," says Baraban. "Basically, any epilepsythat is associated with a single gene mutation can be modeled in zebrafish andthen used in the phenotype-based high-throughput screen we have pioneered.Because zebrafish are intact vertebrates they have an added advantage ofassessing toxicity at the same time, a major problem when moving lead compoundsfrom the bench to the clinic. Zebrafish larvae offer a significant advancementover cell-based assays where whole-animal toxicity cannot be evaluated duringthe drug discovery process."
Seeing as how one pair of adult zebrafish can produceseveral hundred larvae, Baraban notes that "even with a very modest matingschedule it is very easy to screen 20 to 50 drugs per month." In addition, "thezebrafish genome is approximately 70 percent identical to humans, and when oneconsiders only disease-based genes, this number is over 80 percent." Barabanadds that it is also fairly easy to generate zebrafish models of human geneticdisorders.
A few hundred miles east of UCSF, another team is examiningzebrafish in hopes of finding a way to cure deafness. Bruce Riley, a biologyprofessor at Texas A&M University, is taking advantage of the geneticsimilarities between humans and zebrafish to study the latter's inner-eardevelopment.
Zebrafish are among the types of fish considered hearingspecialists, according to Riley. They are able to regenerate hearing, anability 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, thefish's regeneration response can restore that cell within 12 to 24 hours byreactivating early developmental genetic programs. In humans, if a hair celldies, it's gone for good. If the mechanism for controlling this regenerationcan be identified, it could shed light on how to recreate that process inhumans.
In 2010, Riley published a paper detailing that thedisruption of a gene called SOX2 in zebrafish prevents the regeneration of adestroyed 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 ourinability to regenerate lost hair cells is due to a paucity of SOX2.
"Our research is founded on the simple idea that the genesthat 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 haircells, which control hearing. The hope is that if we can understand them, maybewe can figure out a way to coax a similar response out of the equivalent cellsin a human. I absolutely believe that's going to happen in our lifetime. And inprinciple, it could literally be a cure for deafness," said Riley.

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