A 3,000-litre aquatics facility, with the capacity to house 30,000 fish, recently opened in the Black Building. Maintained by the Institute of Comparative Medicine, it provides, for the first time, a centrally supported facility that will allow researchers here to use zebrafish to investigate such areas as environmental toxins and genetic development.
Zebrafish have lifecycles that make them particularly useful for genetic studies, and for studying physiology and the physiological consequences of gene alteration.
“With zebrafish, we can answer questions that are difficult to address using mice or another vertebrate animal model. Furthermore, this in vivo system allows us to make discoveries that would be challenging with cells in a petri dish,” says pediatric cardiologist Kimara Targoff, MD, assistant professor of pediatrics, the first investigator at Columbia to use zebrafish in research.
Targoff uses the zebrafish to understand the genes and molecules that orchestrate heart development and to dissect the mechanisms that go awry. Though the zebrafish heart has only one ventricle and one atrium, the genes that govern heart formation in the fish are also essential in people, so zebrafish can be used to model human congenital heart disease.
Kimara Targoff uses zebrafish to uncover how mutations in Nkx genes, which are commonly found in patients with congenital heart disease, cause structural abnormalities. Without Nkx activity, Targoff has observed that the heart's ventricular cells (orange) transform into atrial cells (green), and ventricular size is reduced compared to a normal zebrafish heart (bottom left photo). The condition is similar to Hypoplastic Left Heart Syndrome (HLHS); by understanding how Nkx genes function in zebrafish, Targoff hopes new therapies can be developed to help patients with HLHS and other congenital cardiac anomalies.
“One of the beauties of zebrafish is their heart develops in two days, and because the embryo is transparent, we can watch the entire process unfold with a microscope,” Targoff says.
The fish are easy to manipulate genetically and researchers can track individual cells through development, permitting examination of size, shape and function.
Once the genes that cause cardiac structural defects are determined, Targoff says there are several potential benefits for future patients with congenital heart disease. For example, for patients with hypoplastic left heart syndrome (HLHS), a deficiency in the systemic ventricular chamber, “using zebrafish, we can learn what causes these problems and test potential therapies,” she says. Targoff observes this loss of ventricular tissue in particular zebrafish mutants and is working to uncover the molecular and cellular basis of this lethal cardiac anomaly.
The idea of repairing the heart with regenerative medicine is also getting a boost from zebrafish research. The genes and molecules that govern cardiac development could be manipulated to transform stem cells into new cardiomyocytes for replacement following myocardial infarction and to augment drug discovery and safety pharmacology.
If you are a researcher interested in knowing more about the Columbia zebrafish facility, contact Urshulaa Dholakia, of ICM, at firstname.lastname@example.org.