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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