Zebrafish may hold key to greater understanding of common diseases.
A two-inch stripy fish that spends its life in the tropical freshwater streams might not seem an obvious target for discovering more about what causes type 2 diabetes, prostate cancer and Alzheimer’s, but according to researchers at Queen Mary, University of London, UK, it could be key to revealing important mechanisms involved in the progression of these diseases.
Zebrafish are like the lab rats of the aquatic world – they develop extremely quickly and the transparent embryos can be grown outside the mother’s body, which allows scientists to observe their organs clearly, making them ideal subjects for assessing how certain substances affect our bodies. In this study, researchers were looking at the effects of zinc. An essential mineral, it is utilised by the body for cell growth, the immune system, brain function, and reproduction. Although scientists believe zinc is key to further understanding of type 2 diabetes, prostate cancer and Alzheimer’s, they’re uncertain as to what its role is.
Zebrafish
Using the zebrafish the researchers were able to develop a sensor that picks up areas in the fish’s body where zinc is present, such as the pancreas, for example. If the researchers can show similar results with the same technique on larger animals and humans, it could prove an effective way to fully understand the role of zinc in disease.
A recent study from the University of Michigan, US, indicates that zinc has the potential to prevent the shut down of insulin-producing cells. The same process also hinders the production of harmful processes involved in Alzheimer’s disease. The Michigan researchers are now hoping to find out exactly how zinc interacts with the body’s other molecules to help prevent diseases such as diabetes. Perhaps the zebrafish will prove to be the key that unlocks the secret.
As this mineral can’t be produced by the body, we need to get it from food. It is possible, however, to take too much: an intake of around 11 mg for a male adult and 8 mg for women is ideal. “Protein appears to aid the absorption of zinc, and it’s found in a wide variety of protein foods,” says registered nutritionist Dr Carina Norris, author of The Food Manual. “Lean cuts of beef, venison, turkey and seafood are excellent sources. You can also get it from vegetarian food sources, such as sesame and pumpkin seeds, but phytate compounds, found mainly high-fibre plant-based foods, hinder the absorption of zinc, so it’s harder for vegetarians to take in enough of this mineral, as they generally eat more phytates.”
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Mount Desert Island in Maine is best known for its lobster shacks, a remarkable concentration of old money (think Rockefellers and Astors), and the legions of tourists who enjoy the hilly, forested wonders of Acadia National Park. But when I visited a few days ago, I was most struck by a remarkable collection of wooden houses in Salisbury Cove, at the north end of the island.
Established 113 years ago to provide a ready supply of creatures for scientific research, the Mount Desert Island Biological Laboratory is one of the few established in the 19th century that still endures. In one tank, dogfish sharks circle round, nosing to the surface now and again. Smaller tanks nearby contain killifish, which have mastered the remarkable feat of enjoying both fresh and salt water. The experts here are studying the proteins the fish use to handle salt, which can provide insights into how our cells perform the same feat – or don’t, in the case of cystic fibrosis.
As I stand next to a smaller tank of skate, Professor Jim Boyer, chairman of the board, explains how he has studied their livers and intestines to understand the “circulation” of bile acids, which are crucial for the digestion of fat in our food.
He is now focused on lampreys, primitive eel-like parasites that use their big sucker-like mouths to latch on to prey and drain their blood. These living fossils have been largely unchanged for 360 million years – and have an ancient quirk that fascinates the professor. In adult lampreys, the plumbing between liver and intestine breaks down, but yet-to-be determined transporter proteins provide alternative pathways for excretion of toxic bile. This could help find treatments for the one in 10,000 babies born with a similar condition, known as biliary atresia.
In a nearby lab, one of Prof Boyer’s colleagues, Dr Voot Yin, is investigating something even more remarkable. He shows me a series of videos: the first opens on a stump, the amputated limb of a salamander. A time-lapse image shows how the limb grows back in only 90 days, matching the original in terms of form and function.
A second video begins with a close-up of the tail fin of a zebra fish, a complex arrangement of blood vessels and various kinds of tissue. Cut the tail off and this complex living fan rapidly grows back in around two weeks.
But perhaps the most remarkable regenerative trick of all can be found in the zebrafish’s heart. It is a simplified version of the one that is beating in your chest, with two chambers rather than four. What is astonishing, however, is its ability to deal with damage.
While the rhythms of a human heart can be sent fatally awry by a little scar tissue or a blocked blood vessel, the fish’s little heart can cope with far more severe injuries. Slice off a decent chunk of the chamber and the heart will start to bleed, before being sealed by a clot. Over the next fortnight, a magical feat takes place: replacement tissue grows back around the rind of the clot, until the organ is restored to its former state
Working with Dr Jerod Denton of Vanderbilt University Medical Centre, Dr Yin is studying the movement of electrically charged calcium ions that surge across the cell membranes, which seem to play a role in this remarkable process of regeneration.
They are also building on earlier work, done by Dr Yin with Dr Kenneth Poss at Duke University Medical Centre, North Carolina which revealed that a reduction in genetic signals based on small scraps of the material RNA – “microRNAs” – is a key step in tissue regeneration.
Because we share a common ancestor with the zebrafish, it is likely that the same mechanisms exist in human cells, too. One day, if this work pays off, they might find a drug that can reactivate pathways that have lain dormant for millions of years, and finally find a way to mend a broken heart.
Scientists are looking to a common zebrafish to learn how the human circadian system functions.
Circadian rhythms — the natural cycle that dictates our biological processes over a 24-hour day —control our sleep-wake process.
Disruptions in the cycle are also associated with depression, problems with weight control, jet lag and more.
They have discovered that a mechanism that regulates the circadian system in zebrafish also has a hand in running its human counterpart.
The zebrafish discovery provides an excellent model for research that may help to develop new treatments for human ailments such as mental illness, metabolic diseases or sleep disorders.
Previous research on zebrafish revealed that a gene called Period2, also present in humans, is associated with the fish’s circadian system and is activated by light.
“When we knocked down the gene in our zebrafish models, the circadian system was lost,” said Prof. Yoav Gothilf of Tel Aviv University’s Department of Neurobiology at the George S. Wise Faculty of Life Sciences.
Gothilf’s team subsequently identified a region called LRM (Light Responsive Model) within Period2 that explains how light triggered gene activity.
To determine whether a similar mechanism may exist in humans, Gothilf and his fellow researchers isolated and tested the human LRM and inserted it into zebrafish cells.
In these fish cells, the human LRM behaved in exactly the same way, activating Period2 when exposed to light — and unveiling a fascinating connection between humans and the two-inch-long fish.
The research appears in the journals PLoS Biology and FEBS Letters