Fishing for Insights into Human Disease

Over the years, zebrafish (and to a lesser extent killifish) have become an important experimental model in biomedical research, thanks to their genetic similarity to humans, transparent embryos, rapid development, and regenerative abilities, among other features. What follows is a look at Columbia researchers who are using these finned wonders to gain insights into human health and disease.

Mending a “broken” heart

Heart attacks are so devastating because once heart muscle is damaged, it doesn’t recover. Affected tissues (usually the heart’s ventricles) undergo scarring and remodeling, processes that limit the heart’s ability to efficiently pump blood. Over time, the heart begins to fail.

But it doesn’t have to be this way, says Kimara L. Targoff, MD, who studies zebrafish, a freshwater species that has an uncanny natural ability to mend a broken heart.

Her most recent research suggests that activation of developmental pathways that are conserved in humans have the potential to promote regeneration in zebrafish hearts.

She found that Nkx genes, notably Nkx2.5, are activated in the zebrafish heart after cardiac injury. “These genes appear to set the stage for the regeneration of cardiomyocytes,” says Targoff, associate professor of pediatrics in the Vagelos College of Physicians and Surgeons.  

It’s as if some of the healthy heart cells in the zebrafish revert to an immature state.

“They’re not quite like stem cells, but they are able to proliferate and then regenerate new heart cells. We’ve shown that Nkx2.5 is required for this to happen,” says Targoff.

Zebrafish hearts and human hearts are not the same, of course. While the former have two chambers, the latter have four. “But they do have many similarities,” says Targoff. “For starters, both have Nkx genes, which would suggest the human cardiomyocytes may have the potential to regenerate. We are trying to figure out how to initiate all the signals to make this happen.”

How does stress impact health?

It goes without saying that life is stressful. Air pollutants, heat waves, traffic jams, work deadlines, relationship issues—you name it—affect our well-being. But exactly how do these stressors translate into poor health outcomes? Brandon Pearson, PhD, uses African turquoise killifish to find some answers.

Like zebrafish, killifish share many genes with humans and breed well in captivity. An added bonus: They age faster than any other vertebrate, reaching sexual maturity in a month, making them a convenient model for studying diseases that can take a lifetime to pan out.

Researchers in Pearson’s lab are using killifish to understand how environmental stressors compromise brain function and contribute to neurodevelopmental disorders such as autism and aging-related neurological disorders such as dementia.

“In one study, we’re trying to figure out how particulates from air pollution contribute to Alzheimer’s disease,” says Pearson, assistant professor of environmental health sciences in the Mailman School of Public Health. “Using particle accelerators and single-cell genetic analyses, we’re able to visualize what elements get into killifish brains and then determine the effects of those elements on the function of individual brain cells.”

Pearson is also using killifish to examine compound stressors, where one stressor affects an organism’s response to another. “Does the first stressor make it more vulnerable to a second one, or make it more resilient? We can actually test this hypothesis by subjecting killifish to compound stressors, such as heat stress coupled with a predator stress,” he explains.

A model for osteoarthritis research

Joanna Smeeton, PhD, became a zebrafish aficionado during her postdoctoral studies, which focused on skeletal development. “Zebrafish are amazing,” she says. “These fish seem to be able to regrow everything: fins, heart cells, spinal tissue, cartilage, ligaments. They have this broad-spectrum regenerative capacity.”

Researchers have been using zebrafish for several decades to investigate everything from birth defects to muscular dystrophy to Alzheimer’s. However, until recently, osteoarthritis researchers had to look elsewhere for an experimental model. Zebrafish joints were thought to lack lubricin, a lubricant that protects the joints of land-dwelling creatures against the forces of gravity and general wear and tear.

Smeeton and her colleagues demonstrated, with advanced imaging and genetic analyses, that zebrafish do in fact produce a form of lubricin, especially in the jaw and pectoral fins. Deletion of the lubricin gene resulted in the same age-related degeneration of joints seen in humans.

Ever since, Smeeton has been using zebrafish to study how stem cells contribute to the regeneration of jaw cartilage and ligaments. Among the questions she hopes to answer: What types of cells are involved in tissue repair? Where do they come from? How do they work together?

“If we can understand how those cells contribute to joint repair, we may be able to awaken similar cells in humans to improve the repair of joints damaged by injury or degenerative disease,” says Smeeton, who is the H.K. Corning Assistant Professor of Rehabilitation & Regenerative Medicine Research (in Rehabilitation & Regenerative Medicine and Genetics & Development) at the Vagelos College of Physicians and Surgeons and a member of the Columbia Stem Cell Initiative.

Can zebrafish teach us how to regenerate neurons?

No one would argue that zebrafish, whose brains are the size of a sesame seed, are smarter than humans. But these tiny aquatic animals can do a few tricks that humans cannot, such as growing scores of new brain neurons in response to neurological pathologies such as Alzheimer’s disease or injury, even well into adulthood. In contrast, once past childhood, humans can manage to regenerate only a smattering of neurons, a rate that declines even more with disease.

Using zebrafish as a model organism, Caghan Kizil, PhD, associate professor of neurological sciences (in neurology and in the Taub Institute) at the Vagelos College of Physicians and Surgeons, is gaining new insights into the molecular mechanisms that underlie neuronal regeneration, or neurogenesis.

“The beauty of zebrafish is that we can get human-relevant experimental results in weeks instead of months or years with other animal models,” adds Kizil. “We can even get these fish to perform memory tests to investigate the cognitive consequences of therapeutic interventions for neurological diseases.”

Thus far, Kizil’s studies have revealed a key molecule (nerve growth factor receptor) that controls nerve regeneration in zebrafish. The same molecule appears to be active in humans during early development but not in Alzheimer’s patients.

“If we could kickstart neurogenesis in humans, we might be able to slow the progression of Alzheimer’s by enhancing the brain’s resilience,” says Kizil. His team has already identified two potential targets for drug therapy. The researchers are designing compounds to selectively hit those targets, which they will evaluate in zebrafish.