A Fishy Tale

Why scientists find fish so fascinating

In the basement of the Biological Sciences Research Building, behind the heavy metal door with the combination lock, it’s always a tropical 82 degrees. The rooms are filled from floor to ceiling with racks of clear plastic tanks. The only sound is the quiet bubbling of oxygen through water.

At first, the tanks appear to be empty, but move closer and you’ll see quick flashes of silver as hundreds of inch-long striped fish dart around. These are zebrafish — more formally known as Danio rerio.

Native to streams and marshes of India, Pakistan and Southeast Asia, they were originally imported for aquariums. Now they have a new home in biomedical research laboratories worldwide.

According to the U-M’s animal census, there were nearly 24,000 zebrafish on campus in 2009. Over the last two decades, the U-M’s fish population has grown as more scientists switch some, or all, of their research from mice to fish. Zebrafish have special advantages that make them particularly valuable for biomedical research.

For example:

• It takes 19-20 days for a female mouse to produce a litter, but a female zebrafish can lay hundreds of eggs that turn into embryos just one to two days after fertilization.
• Zebrafish embryos are transparent and develop outside the mother’s body, so it’s easy to see internal organs as they develop.
• There’s no need to inject zebrafish with experimental drugs. Just add the drug to tank water and the fish will quickly absorb or swallow it.
• Even a small lab can afford its own fish colony and most scientists are happy to donate “starter” fish to colleagues.
• Fish are vertebrates with a backbone and all vertebrates evolved from a common ancestor, so zebrafish and people have a lot in common. Both progress as embryos through the same developmental stages and share similar genes.

Daniel Goldman, Ph.D., a neuroscientist, professor of biological chemistry and research professor in the Molecular & Behavioral Neuroscience Institute, studies genes and signaling pathways that control development of the central nervous system, especially the optic nerve and retina. He was one of the first Medical School scientists to be hooked by zebrafish.

One thing Goldman finds fascinating about zebrafish is their ability to regenerate damaged organs. If you injure the retina of a mouse, the cells die and the mouse goes blind. Injure the retina of a zebrafish and the fish will just grow a new one.

“No one knows why zebrafish retained the ability to regenerate organs or why mammals lost that ability,” says Goldman. “We know that zebrafish have the same retinal cells as mammals, and the genes that regulate regeneration in fish are still present in mammals.” Understanding how regeneration works in zebrafish could be the first step toward finding a way to restore vision in people with damaged retinas.

Goldman has persuaded many U-M scientists to become fish enthusiasts. James Dowling, M.D., Ph.D., assistant professor of pediatrics and communicable diseases and of neurology, is one of them. “I started with 10 fish that Dan gave me,” says Dowling.

Dowling uses zebrafish for research on myotubular myopathy and Duchenne muscular dystrophy. For Dowling, the big advantage of working with fish is that they are almost all muscle. And it’s easy to identify fish with defective muscle tissue.

“Fish have to swim to live; they get their oxygen and food by moving around,” Dowling explains. “Fish that can’t swim normally don’t live more than a couple weeks. Mice, on the other hand, can have a lot of muscle weakness and it doesn’t trouble them that much.”

Mark W. Russell, M.D. (Fellowship 1996), the Aaron Stern Professor of Pediatric Cardiology, uses zebrafish to study a protein called obscurin that organizes and supports skeletal and cardiac muscle fibers as muscle develops in an embryo. “Zebrafish are an excellent model of muscle growth and development,” he says. “Access to the embryos allows you to take cells from one fish and put them in another. You can add or remove genes and then watch the embryos develop to see what happens.”

It may seem like a long way from fish tank to clinic, but U-M scientists say it could be closer than you think. They believe zebrafish have the potential to accelerate the pace of biomedical research and bring about faster, better treatments for human diseases. That makes little Danio rerio a very big fish on campus. —Sally Pobojewski

A Fishy Tale
Other U-M scientists using zebrafish for research

Engineering a Better Hand

Many veterans are returning from wars in Iraq and Afghanistan with amputations. They need prosthetic devices that can restore as much normal function as possible, but most existing robotic devices have limited motor control, no sensory feedback and can be uncomfortable to wear.

The U.S. Department of Defense is funding U-M research to develop a bioengineered nerve interface that could improve the function of prosthetic hands and restore the sense of touch for injured veterans. “Current prosthetic designs were developed decades ago,” says Paul S. Cederna (M.D. 1989, Residency 1997), associate professor of surgery. “We want to make a prosthesis that moves like a normal hand and has the ability to provide sensory feedback.”

Using tissue engineering technology, researchers developed an “artificial neuromuscular junction” made of muscle cells and an electroconductive polymer on a biological scaffold. Initial studies with rats showed the interface relayed motor and sensory impulses and helped nerve endings grow and connect properly. Researchers hope to begin testing the bioengineered scaffold in people within the next few years. —SP

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Celebrex, Low-dose Aspirin Don’t Mix

Millions of Americans who take Celebrex for arthritis or pain control also take a low-dose (81 mg) aspirin every day. Now, Medical School scientists have discovered that drugs like Celebrex interfere with low-dose aspirin’s life-saving ability to prevent blood clots and reduce the risk of heart attack and stroke.

Using X-ray crystallography, researchers found that Celebrex binds to COX-1, an enzyme that promotes clotting, which prevents aspirin’s COX-1-blocking action. In animal studies, researchers found more clumping of platelets — the initial stage of clotting — in blood from animals given Celebrex and low-dose aspirin than in animals given low-dose aspirin alone.

“The greatest risk is for people who take aspirin for cardiovascular problems that are known to be mitigated by aspirin, including patients with unstable angina or those at risk for a second heart attack,” says William L. Smith, Ph.D., the Minor J. Coon Professor of Biological Chemistry. If clinical studies confirm the same effect in people, Smith says it will be important to find a balance in dose or regimens so aspirin and Celebrex can both be effective. —SP

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Diet-Disease Link Intensifies With Age

Good nutrition is even more important for preventing disease in people over 50 than it is for younger adults, according to results from a study directed by Bruce Richardson, M.D., Ph.D. (Residency 1979), professor of internal medicine. The study showed that inadequate amounts of two important dietary nutrients — folate, found in leafy greens, and methionine, found in fish and nuts — led to abnormal gene changes in cultures of immune cells from older adults.

Richardson’s findings suggest that the timing of age-related diseases like heart disease and lupus is connected to an increase in a chemical reaction called DNA demethylation. This process alters gene activity and can “unlock” genes that have been silenced by a related process called DNA methylation. Activating silenced genes at the wrong time can lead to abnormal changes in cells.

To test the effects of nutrient deficiencies on methylation, Richardson and colleagues removed immune cells from blood samples of healthy adults, ages 22 to 81, and cultured the cells with low levels of folate and methionine. Immune cells from adults over age 50 showed abnormal gene changes, while cells from younger adults were not affected.

Maintaining a balance between the dual processes of methylation and demethylation is essential for normal cell function. In previous research, Richardson discovered that DNA methylation decreases with aging, while demethylation increases. He also found that demethylation in immune cells called T cells can contribute to the development of autoimmune diseases like lupus.

Richardson hopes his research will call attention to the importance of a healthy diet for the elderly, as well as lead to clinical trials of folate and methionine supplementation. —CLE

Gene Therapy for Failing Hearts?

The dream of using gene therapy to treat people with heart failure is one step closer to reality, thanks to a recent study by scientists at the U-M and the University of Minnesota. Todd J. Herron, Ph.D., a research assistant professor of molecular and integrative physiology, and others on the research team used an adenovirus to transport genes that regulate muscle contractions into cardiac muscle cells from failing human and rabbit hearts. One of these genes, the fast myosin motor gene, improved contractions of damaged heart muscle cells in the study. —SP

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Cancer’s Inflammatory Connection

U-M Scientists have discovered an important connection between inflammation and breast cancer: a receptor called CXCR1 that triggers the division of cancer stem cells in response to inflammation and tissue damage. In a recent study, scientists found that mice treated with repertaxin — an organ transplant rejection drug that blocks the receptor — had fewer breast cancer stem cells and metastases than mice treated with chemotherapy alone.

“Anti-inflammatory drugs like repertaxin could be a new treatment strategy for targeting cancer stem cells,” says Max S. Wicha, M.D., Distinguished Professor of Oncology. Clinical trials based on this work are being planned. —SP

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Cancer's Stem Cell Revolution

Putting the Brakes on COPD

Chronic obstructive pulmonary disease, or COPD, is a
progressive, debilitating lung disease that affects more than 12 million Americans — mostly smokers or former smokers. The disease causes wheezing, shortness of breath and chest tightening. Breathing becomes more difficult as the disease progresses and there are few effective treatments.

Lung damage begins long before people with COPD are aware of symptoms. By the time they seek medical help, the destructive forces of chronic lung inflammation have taken a heavy toll.

To find ways to detect and treat the disease early, when patients might benefit most, researchers need to understand the immune system’s role in COPD, says Jeffrey L. Curtis, M.D., professor of internal medicine at the Medical School and chief of pulmonary and critical care medicine at the VA Ann Arbor Healthcare System.

Curtis and colleague Christine Freeman (Ph.D. 2006) recently found that excessive activity by dendritic cells — sentinel cells that activate the body’s immune response — could be an important first step in the development of COPD. “If we could alter or stop the action of dendritic cells, perhaps we could stop the disease from progressing,” says Curtis. —SP

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Patient information on COPD