Volume 4, Issue 30 August 2007
Genes to Grow On
All it takes to start a cancer is a single cell's mistake. That error-to proliferate and divide, again and again and again, ad infinitum-is the difference between normal, healthy growth and a potentially fatal tumor.
"The genes that regulate the normal growth of an organism to determine its final size are the same genes that are often mutated in human cancers," says Iswar Hariharan, a UC Berkeley professor of cell and developmental biology. Because these genes are so critical in both development and disease, he says, "We're trying to understand the cellular circuitry that regulates growth."
Hariharan first looked for genes that restrict tissue growth when he was a researcher at Harvard Medical School. There, his laboratory developed a fast and easy method to screen for growth-regulating genes. When these genes are mutated, cells grow better than their neighbors.
Iswar Hariharan gazes into fruit fly eyes to discover genes associated with growth restrictions. Left: a normal fly eye has equal amounts of normal (red) and mutated (white) tissues. Right: Flies with mutations in growth restriction genes have a larger proportion of white, mutated tissue than normal red tissue in their eyes. Photo credit: Iswar Hariharan
Hariharan conducts his research using a classic laboratory subject-the fruit fly-because it is easy to raise and has a well-studied genome. For the growth-gene screen, Hariharan mutates strains of flies, then observes the pattern of cells in each adult fly's retina. In these flies, mutant eye tissue is white, and normal tissue is red. Any fly with a disproportionate amount of white in its eyes must have a mutation in a growth-regulating gene.
Using the screen, Hariharan has identified about 35 genes that cause cell overgrowth. Many have links to human cancers. One gene, archipelago, is mutated in about 17 percent of endometrial cancers and 12 percent of colon cancers. Variants in the gene capicua have been identified in breast cancers.
Once he's identified a growth regulating gene, Hariharan can study what it does. "We're now piecing together the signaling pathways or circuits that cause growth," Hariharan says.
Some of the pathways Hariharan has found appear to detect the concentrations of nutrients inside cells, which might tell cells when they have enough resources to divide. Other pathways may help cells sense the nearness of their neighbors.
"We still have little information on how genes determine the eventual size of the organism or the size of individual organs," Hariharan says. The pathways involved in sensing crowdedness could represent the first genetic links between cell growth and overall organ size.
So far, Hariharan's laboratory has identified genes in at least five distinct pathways that regulate growth. Why these pathways are so numerous, and how they interact, remains unknown.
"In the cases we've tested, the pathways are not interchangeable, suggesting that they each do different things," Hariharan says. "It might be like baking a cake; you have to throw in your eggs and flour and sugar, and throwing in three times as much of one ingredient doesn't help you."
Since Hariharan returned to UC Berkeley as a professor in 2003 (he was a postdoctoral fellow here in the late 1990s), his laboratory has begun to study tissue regeneration.
If unchecked growth can spell disaster, controlled regrowth or regeneration can be a great boon. Understanding how lizards can regenerate their tails, for example, could be the first step in helping humans who have suffered heart attacks replace cardiac muscle.
Although fruit flies can't regenerate tissue as adults, they can, to a limited extent, do so as larvae. The tissue destined to become the fly's wings, known as the imaginal disc, can regrow missing portions if transplanted into a mature female fly's abdomen. Older imaginal discs seem less capable of regeneration. "The tissue has lost its plasticity and has become locked in place," Hariharan says. "We want to look at the growth regulating pathways and try to figure out what changes in them between when the disc can regenerate and when it cannot."
To study this phenomenon, Hariharan's laboratory has developed a strain of fly that can regenerate its imaginal discs without the need for transplantation surgery.
"If we find a gene that when mutated continues to allow regeneration to occur at an older age, that would be very interesting. It suggests there is a mechanism that actively keeps regeneration off," Hariharan says. Such a mechanism may also be present in mammals, as every other growth-regulating gene they've found so far in fruit flies has a mammalian counterpart.
Down the line, drugs targeting this mechanism could conceivably allow patients with severed spinal cords or injured hearts return to good health. Hariharan says, "This is our ultimate dream."