Following the Pathway
But research at MIT’s cancer center extends beyond mice. Plenty of work still continues at the molecular level, with scientists trying to understand how genes and proteins work together to keep cells functioning properly and cancer free. For the most part, scientists are just beginning to understand the biochemical-signal pathways that control cell function. What they’ve learned so far could serve as the foundation for new means of cancer detection and treatment.
Biologist Angelika Amon, for example, studies how chromosomes organize and duplicate within a cell before it divides. Because chromosomes carry genetic information, any flaws in their duplication can lead to cancer, birth defects, or miscarriages. Researchers in Amon’s lab are studying cell division in baker’s yeast, which is similar to that in humans. In fact, says Amon, if a baker’s-yeast cell lacks the gene responsible for a certain process, the corresponding human gene can substitute for it. Amon has identified a key protein that comes into play after the chromosomes in a cell have segregated but before the cell has divided into daughter cells. This protein appears to control the final stages of the process. “The hope is that by learning about the basic mechanisms that control chromosome segmentation, eventually we can learn and understand what goes wrong during cancer,” she says. Amon’s work recently earned her the National Science Foundation’s prestigious $500,000 Waterman award; the stipend will fund further research on the signaling pathways that contribute to cell division.
Some of Amon’s colleagues at the center study the roles of signaling pathways in processes other than cell division. Biologist Michael Yaffe and his group concentrate on the multitude of pathways cells use to communicate information about their growth conditions, their environments, and the integrity of their DNA. When these mechanisms malfunction, they can contribute to cancer by allowing mutant cells with damaged DNA to proliferate. Yaffe’s work in cell signaling after DNA damage has recently uncovered a pathway that could be exploited to make cancer treatments more effective. In January, the group reported that a molecule previously thought to be involved solely in inflammation also affects a pathway used by cells with DNA damage.
In normal circumstances, damage to a cell’s DNA engages several pathways that prevent the cell from dividing while the DNA is being repaired. But the signals in cancerous cells are malfunctioning slightly, so tumors can continue to grow even when their DNA is damaged. Yaffe’s lab showed that disrupting the DNA damage signals still further, by blocking the inflammatory molecule, caused the tumor cells to die. A number of pharmaceutical companies are developing drugs to inhibit the molecule as part of their efforts to combat diseases such as arthritis. “Those anti-inflammatory drugs in development may now have second lives as chemo-sensitizing agents by making cancers much more susceptible to commonly used chemotherapy,” says Yaffe. Experiments to test this hypothesis in animals are already under way.
One of the most exciting new research areas in biology has to do with DNA’s cousin, RNA. One form of RNA, messenger RNA, copies genes’ genetic blueprints and delivers them to cellular structures called ribosomes. Ribosomes in turn use the blueprints to build proteins that do everything from digesting food to forming hair and fingernails to controlling which substances pass through cell membranes.
But other RNAs regulate genes. In just the last five years, biologists have discovered a process called “RNA interference,” in which short strands of RNA target and destroy messenger RNA. What’s more, researchers can chemically synthesize these strands in the lab. “They can be designed to any gene,” says Institute Professor and Nobel laureate Phillip Sharp HM, who is trying to explain the mechanism behind RNA interference. “What the discovery means,” says Sharp, “is that we now have a tool to silence any gene in any cell.” Silencing a defective gene known to be associated with cancer, for example, could prove an effective means of preventing or treating the disease. In 2002, Sharp cofounded the Cambridge, MA-based biotech company Alnylam Pharmaceuticals, which is working to commercialize RNA interference.
One of the biggest challenges Alnylam and other biotech companies face is delivering the chemically synthesized RNA strands to target cells. RNA molecules commonly degrade in the bloodstream before they can reach the desired cells. But last fall, Alnylam reported a new delivery system that could solve this problem. Company researchers were able to trick mice cells into accepting RNA strands by attaching them to cholesterol molecules. When the RNA got inside the cells, it silenced a gene responsible for producing cholesterol, lowering the mice’s cholesterol levels by 35 percent. “The exciting part of this is that if it is real for one gene, it will be real for all of them,” says Sharp.