In a study published last week in the journal Nature, Robert Weinberg and William Hahn of the Whitehead Institute for Biomedical Research in Cambridge, Mass., reported they had succeeded in turning normal human cells into cancerous ones. The transformation wound up requiring the alteration of four genes, including one that had never conclusively been implicated in cancer growth before. The findings–which Nature termed “landmark”–could one day help scientists develop new cancer therapies.
Runaway cell growth is like a car speeding out of control. As with cars, certain defects contribute to the problem. First, the accelerator can get stuck. The equivalent in a tumor is activating an oncogene, which causes cells to multiply rapidly; Weinberg’s team turned on the ras oncogene in their tests. Second, the brakes can fail. In a cell, the brakes are tumor-suppressor genes that regulate growth. Normally, one such gene limits replication of cells and another causes abnormal cells to commit suicide, thereby preventing a malignancy. Weinberg disabled both. But a broken accelerator and brake aren’t enough to cause cancer, and that’s why prior lab attempts had failed. Weinberg succeeded by manipulating a fourth gene–discovered two years ago–that must also go haywire. He compares it to a full tank of gas that lets the runaway car keep on chugging away.
This gene governs the repair of telomeres–short, repetitive sequences of DNA that cap the ends of chromosomes. Telomeres are like the tips on shoelaces that prevent fraying. They help keep chromosomes in order. But each time a cell divides, the telomeres become a little shorter. After a certain number of divisions, the telomeres become so short that a normal cell stops replicating. The cell has reached senescence, or the equivalent of old age. But in a cancer cell, a telomerase gene switches on to rebuild the telomere caps, allowing tumor cells to keep on dividing. Yet scientists still wondered if this was an essential element in tumor formation. The fact that the telomerase gene is activated in 90 percent of human tumor cells might be a mere byproduct rather than cause of human cancer. Weinberg’s research provides the first direct evidence that the telomerase gene is no mere byproduct.
Although Weinberg created cancer by manipulating these four genes, he readily acknowledges that other tumors may arise when different genes are disrupted. His long-term goal is to develop what he calls a “rule book,” showing how different combinations of genes interact in malignancy. That could lead to new treatments, like telomerase-inhibiting drugs, which are already in development. Weinberg’s insights into cancer’s assembly line could one day prove to be a critical step in keeping tumors from ever getting started.
Understanding how cancer starts may one day lead to new therapies. Now, for the first time, scientists have turned normal cells into malignant ones.
A cancer-causing oncogene, when switched on, makes cells divide too rapidly, and two critical tumor-suppressor genes are disabled.
Normal cells cannot divide forever. The ends of their chromosomes are protected by telomeres. With each division the telomeres get shorter, until the cells stop dividing.
In most cancer cells, the telomerase gene is turned on, producing an enzyme that rebuilds the telomeres. This allows the cells to continue dividing indefinitely
