Versatility of zebrafish research highlighted at international conference

June 21, 2012, Genetics Society of America

It's clear where the black-and-white striped zebrafish got its name, but less obvious at first glance is what zebrafish has to do with biomedical research. Amazingly, it has biological similarities to humans, which are making this small freshwater fish an increasingly popular model organism for studying vertebrate development, genetics, physiology, and mechanisms of disease.

The variety of presentations at the 2012 International Zebrafish Development and Genetics Conference, held June 20-24 in Madison, Wisconsin, showcase the breadth of research possible with the zebrafish. Many of these studies are aided by its rapid development, genetic malleability, and optical transparency at early stages that enables imaging of labeled cells within a whole, living embryo.

A small sampling of studies drawing on these strengths is highlighted here.

Watching the Birth and Spread of a Cancer

One of a tumor's most dangerous qualities is its ability to metastasize, or spread beyond its original site. The driving metastasis are an active target of research, often focused on the role of cancer stem cells, which retain a relatively undeveloped state and the ability to multiply.

A research group at Massachusetts General Hospital headed by David Langenau, Ph.D., is advancing this understanding – with a surprising twist – using a zebrafish model of embryonal rhabdomyosarcoma (ERMS), a rare human pediatric cancer of muscle.

The group, led by postdoctoral researcher Myron Ignatius, Ph.D., engineered the fish to contain fluorescent reporter molecules in their tumor cells. The cells fluoresce green when in the stem cell state, turn red as they begin to differentiate, and finally shine blue once they reach their final differentiated identity within the tumor.

As the fish begin to develop tumors – starting at just 10 days old – the researchers can take advantage of the transparency of the young zebrafish to image the cancer process as it unfolds within a whole, living embryo.

"We can visualize the birth of a cancer," Dr.Ignatius says. "How a tumor forms, how tumor cells migrate, and the functional consequences of differentiation within individual cancer cells."

What they saw surprised them. Instead of the expected green stem cells leaving the existing tumor and establishing a new tumor, they saw highly migratory red mid-differentiated cells enter the blood vessels and move to a new site in the body. Over several days, it appeared that the green stem cells then slowly migrated toward the red ones to multiply and form a new tumor. Terminally differentiated blue tumor cells were largely stationary and did not contribute to local .

"Our data support a model where the first cell type to migrate into new areas of tumor growth is not a cancer stem cell, but is paradoxically a mid-differentiated ERMS cell, which has no intrinsic ability to proliferate and remake a tumor. Only after this cell primes the newly colonized area do slow-moving stem cells become recruited and drive continued tumor growth," says Dr. Langenau.

Their results suggest that efforts to control metastatic potential may need to target multiple cell populations within a tumor. Dr. Ignatius suggests, "New therapies should target both the cancer stem cell pool as well as highly migratory cell types that facilitate tumor spread. We believe our zebrafish model of disease will be useful in identifying novel drug targets for both of these processes."

Genetic Factors in Nicotine Dependence and Treatment Success

Nicotine dependence is one of the largest causes of preventable death and is associated with very high health care costs. The few approved treatment options currently available for people looking to kick their habit, primarily varenicline and buproprion, the generic names of two brand-name prescription drugs to stop smoking, have shown moderate success but do not work for all patients.

Professor Stephen Ekker's research group at the Mayo Clinic in Rochester, Minnesota, works closely with the Nicotine Dependence Center.

"We're working together to try to create better treatment options for patients suffering from tobacco dependence," says graduate student Margot Cousin. "There are some patients who receive these treatments and do well, but for other people they have almost no effect. There is a huge amount of variability in that treatment response. We're using the zebrafish model to look for novel candidate genes that might be involved in this process."

Dr. Ekker's lab has created hundreds of zebrafish lines with genetic mutations randomly scattered throughout the genome. Cousin uses a simple behavioral test to look at how the different mutant lines respond to nicotine exposure and drug treatment. Normal fish increase their swimming activity when treated with nicotine, she explains, but pre-treatment with varenicline usually blocks the nicotine response.

As she screens the genetically altered fish, she is looking for those that respond abnormally to either nicotine or the drug. Identification of the specific gene altered in each fish will provide clues to the pathways involved in nicotine addiction.

"We're looking to inform both the science as well as have ramifications for patient treatment. We can gain a lot of knowledge in a relatively short period of time using this as a model," Cousin says.

They hope to expand the available nicotine addiction treatment options to allow a more targeted approach and improve patient outcomes.

Variable Recovery After Chemotherapy

Anti-cancer treatments such as radiotherapy and chemotherapy can have serious side effects due to the death of blood cells, including several types important in the immune system. Those cells can be replenished by regenerative cells in the bone marrow known as hematopoietic stem cells.

"What we know from the clinic is that when people have a hematopoietic injury, such as being treated with chemotherapy, it's important for their to respond quickly to replace what's lost," says postdoctoral fellow Teresa Bowman, Ph.D. But, she adds, "There's huge variation between people, and it's largely unexplored why."

Bowman, who works with Leonard Zon, M.D., at the Boston Children's Hospital, is exploring the genetic basis underlying the differences between individuals, using zebrafish as a model system.

She observed that two common strains of zebrafish recover from radiation exposure at very different rates. "This is a great model for what we know to be true in humans, that one group responds slowly and one group recovers faster. We can use this to look at the genetic basis of this difference," Dr. Bowman says.

By inter-breeding the two strains of fish, she can correlate the speed of response in the offspring with the gene variants inherited from each parent strain. To date, she has identified three regions in the genome that seem to be linked with the speed of hematopoietic recovery.

It is likely that there are multiple genes involved, and she is now planning a whole-genome sequencing project to identify additional sites and hone in on the individual genes underlying naturally occurring variation in hematopoietic regeneration processes. Such genes may provide therapeutic targets for boosting recovery following chemotherapy or radiation treatments.

Explore further: Cancer cells: Some types control continued tumor growth, others prepare the way for metastasis

More information: www.zebrafishgenetics.org/

Related Stories

Cancer cells: Some types control continued tumor growth, others prepare the way for metastasis

May 15, 2012
A study from Massachusetts General Hospital (MGH) researchers suggests that specific populations of tumor cells have different roles in the process by which tumors make new copies of themselves and grow. In their report in ...

Study identifies gene critical to development and spread of lung cancer

April 24, 2012
A single gene that promotes initial development of the most common form of lung cancer and its lethal metastases has been identified by researchers at Mayo Clinic in Florida. Their study suggests other forms of cancer may ...

Recommended for you

Group recreates DNA of man who died in 1827 despite having no body to work with

January 16, 2018
An international team of researchers led by a group with deCODE Genetics, a biopharmaceutical company in Iceland, has partly recreated the DNA of a man who died in 1827, despite having no body to take tissue samples from. ...

The surprising role of gene architecture in cell fate decisions

January 16, 2018
Scientists read the code of life—the genome—as a sequence of letters, but now researchers have also started exploring its three-dimensional organisation. In a paper published in Nature Genetics, an interdisciplinary research ...

How incurable mitochondrial diseases strike previously unaffected families

January 15, 2018
Researchers have shown for the first time how children can inherit a severe - potentially fatal - mitochondrial disease from a healthy mother. The study, led by researchers from the MRC Mitochondrial Biology Unit at the University ...

Genes that aid spinal cord healing in lamprey also present in humans

January 15, 2018
Many of the genes involved in natural repair of the injured spinal cord of the lamprey are also active in the repair of the peripheral nervous system in mammals, according to a study by a collaborative group of scientists ...

The coming of age of gene therapy: A review of the past and path forward

January 11, 2018
After three decades of hopes tempered by setbacks, gene therapy—the process of treating a disease by modifying a person's DNA—is no longer the future of medicine, but is part of the present-day clinical treatment toolkit. ...

Large-scale study to pinpoint genes linked to obesity

January 10, 2018
It's not just diet and physical activity; your genes also determine how easily you lose or gain weight. In a study published in the January issue of Nature Genetics, researchers at the Icahn School of Medicine at Mount Sinai ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.