April 14, 2016

WHAT’S UP DOC? | Small Fish Make a Big Difference

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Have you ever thought about the functions of the thousands of genes inside our bodies? Scientists have been excited to answer this question ever since the Human Genome Project identified more than 20,000 genes, most of which were of unknown function. The past decade has witnessed a great explosion of knowledge about gene function and regulation. Most of this knowledge has come from studying model organisms, ranging from single-celled yeast to multi-whiskered mice. Since the fundamental biological processes are amazingly conserved across different species, studies from model organisms have taught us a lot about how our own bodies work and have led us to develop methods to treat diseases.

One such model organism, the tiny zebrafish, has attracted a lot of attention in the past 20 years for its versatile contributions to science. Originally found in freshwater streams in Asia, the zebrafish was first developed as a model organism by George Streisinger in the late 1960s. In addition to their rapid development, zebrafish are small in size and easy to maintain in research facilities. Each zebrafish mating produces hundreds of embryos to work with. The most amazing feature of zebrafish is that their embryos develop externally and are almost transparent. As a result, scientists can observe the entire developmental progression from a single cell to a larva in a dish!

The many advantages of zebrafish make them ideal for geneticists and developmental biologists to study gene function. A classical way scientists have interrogated the function of a gene by randomly introducing mutations in genes simply by adding mutagenic chemicals into fish water. By studying developmental abnormalities that develop in these mutant fish, we can understand the functions of the genes that they are mutant for. Using this method, Christiane Nüsslein-Volhard and colleagues led the pioneer massive screens in the early 1990s and identified thousands of genes that are important for development, many of which are conserved in humans and expected to execute similar roles in human development. These screens had the limitation that we did not have control over which genes would be mutated. However, we have now come a long way to overcome this randomness. Scientists have developed ways to introduce mutations very specifically in the gene they are interested in and study the consequences of such disruptions to unravel the function of a specific gene. Given that around 70 percent of human genes have at least one similar gene in zebrafish, understanding functions of genes in zebrafish have been and will be useful to understand how humans work.

Beyond answering the very basic questions in biology such as gene function, zebrafish have also provided new insights into human health.  As the immune system in zebrafish is similar to that in humans, many human infectious diseases are being studied in zebrafish. Tuberculosis is a dangerous global infectious disease caused by Mycobacterium tuberculosis and kills 1.5 million people per year. Mycobacterium species also infect zebrafish and cause similar disease symptoms as in humans. Exploiting the optical clarity of zebrafish embryos, fluorescently labeled pathogens have been traced in real time after infecting the zebrafish. This has furthered our understanding of how pathogens spread as tuberculosis develops and how host immune cells respond to pathogens. Granulomas are hallmark structures of tuberculosis characterized with aggregated immune cells. Tuberculosis granulomas have been long considered to resist mycobacterial growth. Studies in zebrafish have shown otherwise as granulomas in fact facilitate bacterial growth by disseminating infected host immune cells. These studies have provided a new antituberculosis therapy by targeting the formation of granulomas.

Zebrafish also have an extraordinary ability to regenerate various cells and tissues. When zebrafish heart is damaged, the wound is quickly sealed and new heart muscle cells gradually replace the damaged site, rebuilding a fully functional heart. In contrast, the human heart is unable to regenerate new muscle, resulting in compromised heart functions after damage. Scientists have been curious to understand why zebrafish heart and human heart have such different regenerative abilities, despite their functional similarity. For example, studies have reported that the expression of certain key cell cycle factors are turned up to promote heart regeneration, assuring the massive proliferation of heart muscle cells to mend the broken heart. If scientists can switch on the same set of genes in human that allow zebrafish to regenerate their heart tissues, people may have better clinical outcomes after heart attacks and heart injuries.

Last but not least, zebrafish has become a popular model to study many types of cancer. Zebrafish develop cancer spontaneously when exposed to a carcinogenic environment. As many genes are shared between zebrafish and human, human cancer-causing genes or human cancer cells often culminate in similar cancer phenotypes once introduced into zebrafish. Scientists have successfully generated leukemia, melanoma, pancreatic and liver cancer models in zebrafish to study tumorgenesis in the context of different genetic backgrounds. Metastasis, the spread of cancer cells from the primary site to distant sites, is an intrinsic feature of many cancers. Metastasis remains the primary cause of death of cancer patients and the nature of metastasis is still poorly understood. Zebrafish provide a new approach to tackle the question. The translucent skin of zebrafish allows scientists to transplant fluorescently labeled tumor cells into zebrafish. The spread and seeding of cancer cells can be characterized subsequently with a microscope at single cell resolution. Using zebrafish cancer models, scientists have shown that knockdown of certain genes in human cancer pancreatic cells decreased invasion and metastasis. In addition, zebrafish cancer models have also shed light on cancer treatment. Through screening a library of 2,000 chemicals, leflunomide, which is originally used for patients with rheumatoid arthritis, shows potent ability to inhibit the growth of human melanoma cells. This discovery will be instructive to further screens in zebrafish to uncover new inhibitors of tumor growth and metastasis.

Over the past two decades, we have already learned a lot from the zebrafish. With the soaring popularity of zebrafish model and more investment on zebrafish research, our vertebrate relative is going to tell us more about who we are and where we are going.

Cheng Li is a fifth year PhD candidate at Weill Graduate School of Cornell University in New York City. He may be reached at chl2030@med.cornell.edu. What’s Up Doc? appears alternate Fridays this semester.

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