Kenneth Irvine intended to major in political science when he went to Williams College, but an undergraduate project on RNA sparked an interest in biochemistry. Then as a graduate student at Stanford in the mid-1980s, he became excited about animal development. "It was amazing to think that you could find single genes that have such important roles in controlling the way an organism develops," says Irvine, who, while doing his Ph.D., discovered a faulty fruit fly gene, fringe, that affects wing development.
As a postdoc at Princeton and an independent researcher at Rutgers, Irvine cloned the fringe gene and determined how the normal version contributes to wing formation. In the late 1990s, he was surprised to discover that fringe encodes an enzyme that tags certain proteins with a sugar, changing the way they receive signals from other proteins. At that time, sugars were not known to influence developmental signaling. "I never thought I would be working on sugar biology," says Irvine, who rushed out to buy a textbook on the subject.
His research showed that the Fringe protein regulates a signaling pathway called Notch, allowing it to operate only on the boundary between the dorsal and ventral compartments of the wing-to-be. As a result, cells on either side of that boundary interact, causing specialized cells to sculpt the wing's edge. "One of the things I like about the fringe project is that it has taken us from discovering the gene, through a whole series of steps aimed at understanding—at the genetic, molecular, and biochemical levels—the processes that explain the phenotype of this funny-looking fly," Irvine says.
Later studies by Irvine and others showed that fringe also helps create tissue boundaries during eye and leg development and that it has maintained that function during evolution. In humans, a faulty fringe gene can misshape vertebrae.
Over the years, Irvine's lab has increasingly focused on the relationship between developmental patterning and the proliferation of cells that is necessary for growth. "Different organs and appendages grow to different sizes, so we think there is a link between the way you tell different cells where they are and what type of cell they are supposed to be and how much that tissue grows," Irvine says.
Interest in this question led his group to discover and characterize a Fat signaling pathway, named for a Drosophila mutation that results in shorter, wider flies. One branch of the pathway influences planar cell polarity. "This type of polarity reflects the overall coordinates of a tissue, as if, for example, every cell in your hand knows which direction points to your fingers and which to your shoulder," Irvine says.
The pathway's other endpoint involves the regulation of gene transcription. Irvine's group showed that Fat signaling intersects with another signaling system, the Hippo pathway, to regulate sets of genes that control several aspects of development, including tissue growth and cell death.
His interest in the relationship between organ patterning and organ growth led to studies of another signal, decapentaplegic (DPP), which is required for growth of all the fly's appendages. DPP was known to be a morphogen—a substance that diffuses from one part of a tissue to directly affect cells according to its concentration. Thus, cells near the source of DPP have one fate, whereas those farther away have others. DPP controls both growth and patterning. "But people had not understood how the growth-promoting activity related to DPP's influence on tissue patterning," Irvine says.
His group showed that growth depends not only on the amount of DPP that reaches a cell but also on how much that cell's neighbors receive. "So if I am next to a cell that receives a lot more or a lot less DPP than I did, that provokes some type of growth-promoting signal," Irvine explains.
The researchers then discovered that the gradient of DPP controls the expression of some of the genes in the Fat signaling pathway. "So we think that one of the things the Fat pathway is doing is linking a gradient of a morphogen, such as DPP, that patterns tissue to the actual growth of an organ [such as the wing]," Irvine says.
One of his most surprising findings to date is that a gene called four-jointed, which helps regulate the Fat pathway, is a Golgi kinase. The Golgi apparatus, a stack of membrane-bound sacs, packages large molecules for shipment to other parts of a cell or for secretion. A kinase is an enzyme that adds phosphate groups to other molecules, often as part of a signaling pathway. Before Irvine's work, no kinases had been identified in the Golgi apparatus. His group has since identified other Golgi kinases that may be involved in bone formation.
"A year ago, I had no idea that I would be thinking about bone," Irvine says. "But that is one of the great things about being a scientist. You can make an unexpected discovery that leads you to think about a new field and then set out in a completely different direction."