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Models of Transparency

Models of Transparency

Heath, J.K. Langenau, D. Sadler, K.C. and White, R. (2013) Models of Transparency. The Scientist.

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Researchers are taking advantage of small, transparent zebrafish embryos and larvae—and a special strain of see-through adults—to understand the development and spread of cancer.

The zebrafish model offers a major opportunity to discover impor­tant pathways underlying cancer and to identify novel therapies in high-throughput drug screens, in a way that mice never could.

From frogs to dogs and people, cancer wreaks havoc across the animal kingdom—and fish are no exception. Coral trout, for example, develop melanoma from overexposure to sun, just as humans do. Rainbow trout develop liver cancer in response to environmental toxins. And zebrafish—small, striped fish indigenous to the rivers of India and a widely used model organism—are susceptible to both malignant and benign tumors of the brain, nervous system, blood, liver, pancreas, skin, muscle, and intestine.

Importantly, tumors that arise in the same organs in humans and fish look and behave alike, and the cancers often share common genetic underpinnings. As a result, most researchers believe that the basic mechanisms underlying tumor formation are conserved across species, allowing them to study the formation, expansion, and spread of tumors in animal models with the hope of eventually finding new insights into cancer in people.

Zebrafish are an increasingly popular choice among cancer biologists. Between 1995 and 2012, there was a 10-fold increase in the number of yearly PubMed citations of cancer studies in the species, with more than 200 research papers published last year.  Although dwarfed by cancer studies using human tissue and mouse models, the optical transparency of zebrafish embryos and larvae—and now, adult fish of a recently created strain—allows researchers to track tumors in a way that is not possible in other vertebrate models. Furthermore, their small size—embryos are small enough to be reared in 96-well plates—make them a more practical laboratory system than other cancer models. Indeed, researchers are now using these fish to identify druggable oncogenic drivers of specific tumor types, to tease apart the complex network of cancer genes that cooperate in tumor formation and progression, to probe the interplay between the genes that govern embryonic development and those that cause cancer, and to uncover how tumors metastasize and kill their host. The zebrafish model offers a major opportunity to discover important pathways underlying cancer and to identify novel therapies in high-throughput drug screens in a way that mice never could.

Z ebrafish (Danio rerio) have fast made their way from pet stores and home aquaria into research laboratories worldwide. Their weekly matings produce 100 to 200 embryos that rapidly and synchronously march through embryonic development, so that within 5 days of fertilization, they are mature, feeding larvae. Zebrafish are small and inexpensive to maintain in high numbers, facilitating large-scale experimentation and cheap in vivo drug screens. Famously, the fish are transparent during early larval stages, allowing investigators to directly observe internal development and making the fish a favorite of developmental biologists since the 1960s. But in recent years, the utility of zebrafish has been proven beyond developmental fields, and they are now being found in more and more laboratories studying behavior, diabetes, heart disease, regeneration, stem cell biology—and cancer.

Critically, zebrafish can be used to identify the important pathways and processes that cause cancer in people. Common organ systems and cell types are shared between human and zebrafish, and whether induced by transgenesis or carcinogens, cancers arising from the blood (leukemia and lymphoma), pigmented cells of the skin (melanoma), and the cells that line the bile ducts (cholangiocarcinoma) have microscopic features that are essentially indistinguishable between humans and zebrafish.

The zebrafish model offers a major opportunity to discover impor­tant pathways underlying cancer and to identify novel therapies in high-throughput drug screens, in a way that mice never could.

Comparing gene-expression profiles of tumors across various species provides a powerful mechanism for identifying genes that likely represent core functions of cancer. For example, microarray gene-expression analyses have compared the gene signatures of fish hepatocellular carcinoma to that of human liver, gastric, prostate, and lung tumors. Remarkably, this analysis revealed that fish and human liver tumors are more similar to each other than either tumor type is to human tumors derived from different tissues. Moreover, comparative studies can often be used to pinpoint pathways that are active in human disease. This is illustrated by work on a zebrafish model of rhabdomyosarcoma (RMS), a cancer of skeletal muscle, which revealed a gene signature that is also commonly found in human RMS, highlighting the importance of the RAS signaling pathway in the genesis of human RMS

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Seasonal Flu Outbreaks

UMaine Study the First to Establish Zebrafish as Model for Studying the Influenza Virus

University of Maine. (2014) UMaine Study the First to Establish as Model for Studying the Influenza Virus. UMaine News.

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In the ongoing struggle to prevent and manage seasonal flu outbreaks, animal models of influenza infection are essential to gaining better understanding of innate immune response and screening for new drugs.

“A zebrafish model of IAV infection will provide a powerful new tool in the search for new ways to prevent and treat influenza,” according to the researchers, who published their findings in the journal Disease Models & Mechanisms.

In the ongoing struggle to prevent and manage seasonal flu outbreaks, animal models of influenza infection are essential to gaining better understanding of innate immune response and screening for new drugs. A research team led by University of Maine scientists has shown that two strains of human influenza A virus (IAV) can infect live zebrafish embryos, and that treatment with an anti-influenza compound reduces mortality.

It is the first study establishing the zebrafish as a model for investigating IAV infection.

The research team is led by professor Carol Kim and graduate student Kristin Gabor of UMaine’s Graduate School of Biomedical Sciences and Engineering, and includes four other UMaine researchers and one from Ghent University.

Most studies of viral pathogens that can infect zebrafish have been limited to fish-specific viruses. However, in recent years, four human viral illnesses have been reported to be modeled in zebrafish — herpes simplex, hepatitis C and chikungunya and now influenza A.

For studies of flu virus infection, the researchers focused on specific sialic acids and cytokines comparable in zebrafish embryos and humans. For these studies the zebrafish embryos also were kept in a temperature range comparable to the human respiratory tract (77 to 91.4 degrees F).

“The transparent zebrafish embryo allows researchers to visualize, track and image fluorescently labeled components of the immune response system in vivo, making it ideal for immunological research,” said Kim, a UMaine microbiologist and vice president for research and graduate school dean, writing earlier this year in the journal Developmental and Comparative Immunology

In addition, the antiviral drug Zanamivir, known for being effective in treating influenza A and B in humans, was tested in vivo and was found to reduce IAV infection.

The researchers note that studies of IAV infection in adult zebrafish have the potential to provide valuable insights into infectious disease processes, particularly in understanding adaptive immune response and vaccine efficacy. This is critically important in light of the rapidly developing resistance of the influenza virus to drug therapies.

“This zebrafish embryo model of IAV infection will be an important resource for dissecting molecular mechanisms of host-pathogen interactions in vivo, as well as for identifying new antiviral therapies,” write the researchers.

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How Pathogens Become Killers

Wheeler Awarded $500,000 to Study How Common Pathogens Become Killers

University of Maine. (2014) Wheeler Awarded $500,000 to Study How Common Pathogens Become Killers. UMaine News.

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How does a normally peaceful agent break through a previously
impenetrable barrier and become a potential killer?

Robert Wheeler has just received a five-year, $500,000 fellowship from the Burroughs Wellcome
Fund (BWF) to figure that out.

The University of Maine Assistant Professor of Microbiology will study how and why Candida albicans — the most common human fungal pathogen — transforms from an innocuous yeast in the digestive tract of a person with a healthy immune system to a potentially fatal fungus in vital organs of a person whose immune system has been compromised.

“This award marks a new high point in my research career,” says Wheeler, one of 12 scientists nationwide to receive the 2014 Investigators in the Pathogenesis of Infectious Disease Award. After internal competitions at colleges and universities, each institution may nominate two investigators; this year, 144 scientists were put forward.

T“This provides substantial funding that we can use to pursue high-risk projects with the potential to change our perspective on how dangerous infections begin.”

The goal, he says, is to improve diagnosis and therapy of fungal infection due to better understanding of the interactions between host and pathogen cells.

Wheeler’s lab will explore the host-fungal dialogue at mucosal surfaces where C. albicans — the leading cause of hospital-acquired infection that annually kills several thousand patients in the U.S. — is normally kept in check. “We expect that this will allow us to understand how the healthy immune system normally inhibits infection and how C. albicans invades past the epithelial wall,” he wrote in his application.

What happens at the earliest stages of active infection is one of the biggest mysteries about opportunistic pathogens, he says. And solving that mystery is imperative as infections complicate treatment of diseases, including leukemia, that require suppressing the immune system.

Wheeler’s lab will use zebrafish models of candidiasis at multiple levels — holistic, cellular and molecular genetic — to investigate the interaction between fungal cells and host cells during the earliest stages of infection. The integrated approach will utilize a new set of tools to address questions that have previously been inaccessible, he says.

His lab already has conducted pioneering studies with transparent zebrafish, which model infections caused by bacterial and fungal pathogens of humans. The resulting findings, he says, “opened the door to a deeper understanding of host and pathogen activity at the beginning stage of infection.”

Wheeler credits the previous scientific breakthroughs, and the work on the grant, to the talented, highly motivated and hard-working students and post-doctoral fellows in the laboratory. “The award is based on the pioneering work that they have done to change our perspective on fungal infection over the last five years,” he says.

With this fellowship, Wheeler says his lab will seek to exploit “that opening to discover the mechanistic underpinnings of the dialog between C. albicans and innate immunity at the epithelial barrier.”

On a personal level, Wheeler says he’s humbled to join the creative group of scientists that have previously held or currently hold BWF grants. “It pushes me to further excel and tackle the most important problems in infectious disease,” he says.

Wheeler’s peers lauded both his prior research and his potential.

Aaron Mitchell, professor in the Department of Biological Sciences at Carnegie Mellon University, says Wheeler has “been an insightful innovator for his entire scientific career.”

This award, Mitchell says, will allow Wheeler to build upon his initial findings “to look at the way that the host manipulates the pathogen, and how the pathogen manipulates the host. The remarkable zebrafish toolbox will allow Rob to look for key features of host defense that we can strengthen to thwart the pathogen before it gets a foothold.”

Joseph Heitman, chair of the Department of Molecular Genetics and Microbiology at Duke University Medical Center, says Wheeler’s research on how “Candida albicans … shields its immunogenic cell surface from immune surveillance in a variety of ways, which can in part be circumvented by drugs that unveil immunogenic signals” has blazed trails.

Heitman says the award will allow Wheeler, a “highly creative and innovative” investigator, to continue to be a leader in the field.

Gerald Fink, the Herman and Margaret Sokol Professor at the Whitehead Institute/Massachusetts Institute of Technology, says the award “recognizes [Wheeler’s] preeminence as a leader in the battle to combat Candida, a feared human fungal pathogen … for which we have no satisfactory protection.”

Fink anticipates Wheeler’s research will “provide critical insights into our natural immunity from Candida infections, which is the first step towards developing antifungal agents.”

And Deborah Hogan, associate professor in the Department of Microbiology and Immunology in the Geisel School of Medicine at Dartmouth College, says, “Ultimately, this work is likely to provide important insight into better ways to prevent and fight these often dangerous infections” in babies, in people undergoing chemotherapy and in those with suppressed immune systems.

The first installment of the award will be sent to UMaine on July 15, according to BWF, an independent private foundation based in North Carolina that supports research to advance biomedical sciences.

Victoria McGovern, senior program officer at BWF, says Wheeler’s selection was “based on the scientific excellence and innovation” of his proposal, as well as the strength of the scholarship at UMaine and Wheeler’s accomplishments as a researcher.

Wheeler says he’s pleased the award showcases UMaine and the laboratory to the national research community and he’s excited for opportunities to be in “contact with a number of the best and brightest infectious disease investigators in the U.S., through yearly meetings and a number of networking opportunities at national conferences.”

 

“The University of Maine is very proud of Dr. Wheeler’s achievement,” says Carol Kim, UMaine vice president for research.

“The BWF is a very prestigious award and identifies Rob as a leader in his field.”

 

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