Feeling better? Say thanks to the fruit fly, the zebrafish, the mouse
Mike Terry, Deseret News
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SALT LAKE CITY — Watch a life-saving drug flow into the arm of a loved one who has cancer or reach for prescription medication to ease your allergies or lower your blood pressure and there's a good chance you owe some thanks to a fruit fly, a zebrafish or a mouse. Or maybe all of them.
It's unethical to experiment on humans; the road to helping them has been paved with yeast, worms, flies, fish and mice, among others. Worms are easier to manipulate than fish, which are easier than mice — the beginning of research in mammals — which are easier than humans.
It's what they have in common that has proven beneficial: protein-coding genes.
For instance, of the fruit fly's 14,000, half are the same in humans. Zebrafish and humans both have about 25,000, many of them the same. Mice are even more similar genetically to humans, says Dr. Mary Beckerle, CEO and director of the Huntsman Cancer Institute. Research in one can offer insights into the others.
President Richard Nixon declared war on cancer 40 years ago. But it hasn't been cured because, it turns out, cancer is more than 200 different diseases — some with effective treatments now and even cures, some not. Some cancer can be lived with as a chronic disease. Still others are most often a death sentence. But consider this: Where 50 years ago childhood leukemia killed more than 95 percent of its victims, 80 percent now survive. The research is building futures.
And cancer is just one example. AIDS was always deadly. Now, "overall, survival is way up. It's a difficult life, but you can survive," says Carl Thummel, professor of human genetics at the University of Utah and an expert in the fruit fly Drosophila.
Progress in individual diseases has hinged on studies that moved through a hierarchy of creatures, from simplest to more complex, until there was enough known and enough promise to justify human testing.
Humans also have a role in early research, using a population database and genetic samples from people with particular conditions. With those, researchers seek defects in the same genes in multiple people. It's part of the patchwork of building treatments and furthering scientific understanding of what happens when the body works well and when things go wrong.
But that's looking back at what happened. To look forward requires a model system that's alive, whether it's yeast or a mouse. "You can't do a human experiment to answer a precise question," Thummel says. "This is the next best thing. Working with simple animals provides a bedrock of research and scientific discovery."
For instance, the nematode worm, C. elegans, has been invaluable to scores of researchers for how well it explains the basics of how cell numbers are regulated during development, says Dr. Nikolaus Trede, associate professor in the Department of Pediatrics at the U. School of Medicine and a HCI investigator.
Thummel calls the worm essential to understanding the nervous system, too.
For a long time, the cause of cancer was fodder for wide-ranging theories: It's a virus. No, it's a pathogen.... In the late '70s and early '80s, research suggested that genetic changes could cause cancer. The RAS gene, a major regulator of normal cell growth, was implicated in bladder cancer. In flies, mutations in the RAS gene revealed a major pathway controlling cell growth and proliferation. The work was bolstered by worm studies that gave important insights into how RAS controls growth.
When it was shown that some cancer resulted from such cell growth run amok, cells proliferating too quickly, it was assumed that accounted for all cancer types. But worm researchers found that the failure of appropriate cell self-destruction, called apoptosis, controls cell number. Some cancers, like leukemias, are caused by that misregulation of cell death pathways.
Major cancer pathways have been explored and worked out in flies, worms, mice. The signaling pathways of human development were learned from yeast, worms, flies. When researchers looked at roughly 300 genes in humans known to cause diseases when mutated, 60 percent of those genes were also found in fruit flies, Beckerle says. When scientists looked at known human cancer-causing genes, more than 70 percent were present in the fruit fly, too.
Scientists verify a gene is the same across animal types in various ways. "The first experiment is on the computer, before the experiment in the lab," Beckerle says.
Once a gene that causes human disease is identified, scientists can search gene databases to see if that gene is present in a model organism. Next, they remove the gene from a worm, fish, fly or mouse or introduce a modified version of the gene and see what happens.
In an invertebrate creature like a fruit fly, it's not unethical or as difficult to study the mechanisms of disease. They lack a political lobby and don't attract much concern. You can't study those pathways in the same way in humans. You can't engineer human model systems. But the researchers note that institutional committees create high standards for research involving vertebrates, like fish and mice. Thummel says that ensures they are used only when necessary and under humane conditions.
Researchers have learned much of what they know about development from the eye of fruit flies. Insights include how a highly specialized cell emerges from something undifferentiated, turning a fertilized egg into an infant. Knowledge keeps growing.
The other "huge advantage of flies, worms and zebrafish" is you can see the process in real time under the microscope. Generations and life cycles are much, much shorter. Changes happen faster, crucial to move research forward, Beckerle and Trede say.
They are also plentiful. A fruit fly, for instance, has several hundred offspring on a two-week cycle, says Thummel, who uses them in diabetes, obesity and circadian rhythm research, among others. He quips that he chose fruit fly research because he's too impatient to study animals with slower life cycles.
The simpler the animal, the cheaper the research is.
Both collaboration and competition mark such genetic research. But as Beckerle notes, researchers also build upon each others' findings. Collaborations between departments, institutions, even specialties is common and fruitful.
The results can be powerful, she says. The gene that causes most colon cancers in humans is called APC. In model systems (where the equivalent of a human disease is created in an animal to learn about it and perhaps shed light on potential cures) the biochemical pathways APC controls were found, affording opportunities to study both how it should work and what can go awry.
Of all childhood cancers, 15 percent are bone cancers called sarcomas. "We know a lot about the genetic changes that cause sarcomas," says Beckerle. Less is known about how to treat them effectively. One barrier is the need for good pre-clinical models.
In the fly, the mouse, the fish, researchers are unlocking secrets that lead to therapy, medications, even prevention of disease. But Thummel says some view the war on cancer as a failure. And they think of research in organisms and simpler animals "as a joke."
Scientists aren't laughing. They view the discoveries with fascination, excitement — and hope.
Although so many genes are the same, they don't just do the same things across the different creatures. A gene crucial to wing development in a fly might help build an organ in a human. And it has been shown that genes can serve multiple functions.
It is the different ways that the genes are used that informs knowledge, Beckerle says. Ditto the difference in defects a mutation can cause. One mutation in the C. elegans worm kills it; in a fly, eyes don't form with the same mutation but the creature lives.
Sometimes, says Trede, the unexpected result provides the greatest insight. That happened when researchers tried to make a model of one leukemia and instead created a different kind of sarcoma.
The fish proved to be a particularly useful creature for sarcoma research, Trede says. Local spread of Rhabdomyosarcoma can be observed in zebrafish. That's impossible in mice or humans.
There are many types of sarcoma, not all with an effective treatment. The barrier is lack of a pre-clinical model of the disease in the animal. One effort in its infancy is research on translocations — think of a chromosome as a large X with the ends of each cross bar broken off and then reassembled on the wrong bar.
Translocations are being studied extensively in the lab of Mario Capecchi, a U. genetics researcher who shared the 2007 Nobel Prize in Medicine for creating a way to knock out genes in mice. That's essential to use them to model diseases. Mice, says Beckerle, are an "incredibly powerful mammalian model for human disease."
To be sure, she adds, a potential therapy in a mouse is not proof it will work in humans. But the more closely the mouse model of a disease resembles the human version, the better the chances.
To skeptics who criticize the utility of mouse models, Beckerle says she believes failures often result from imperfect disease replication.
Some model systems are also exceedingly helpful for "drug screens," where compounds are tested sometimes randomly to see what might have an effect on a particular gene mutation or disease. The Trede lab at HCI uses zebrafish to test compounds from big chemical libraries to see if they can find the effects they desire, such as activity against leukemia. Compounds are added to the water in which zebrafish swim. That also tells researchers something about absorption of a potential future drug. They can screen hundreds of thousands of compounds and combinations.
A promising drug to treat leukemia, for instance, was first identified in their zebrafish screen, targeting a specific cell that can develop the disease. For such research, scientists routinely label cells with a glow-in-the-dark green protein so they can see the effect under the microscope, a kind of light show on the fishes' organs.
In colon cancer research, David Jones, HCI scientist, genetically engineered zebrafish so they carried the mutant form of APC that causes human colon cancer, then looked for and found compounds that would kill cells with mutant APC, while leaving normal cells alone.
Because the time from a lab bench to a pharmacy shelf is long, it's unlikely today's research will save today's disease sufferer. But researchers are hopeful the next generation will benefit.
Typically, it takes up to 15 years to move something promising as a treatment through the process to being marketed, Trede says. Advances that allow screening in model organisms rather than in cell cultures may reduce that because of what's learned about a potential drug, such as if it is toxic and whether it can be absorbed.
"The hope is we're becoming smarter and moving faster, with fewer failures," Beckerle says.
With each new breakthrough in knowledge of how genes work, of how to screen, "We hope, we pray, we believe" results will be more certain and more swift, she says.
For researchers, there is quite literally no time like the present, Thummel says. Knowledge is "snowballing." In what he calls a "particularly exciting time, when you answer one question, it opens lots more doors to new research and new discoveries."
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