Cell Biology, Genetics
European Institute of Oncology
Dr. Visintin is a group leader in the Department of Molecular Oncology, European Institute of Oncology, and an assistant professor at the European School of Molecular Medicine, Milan, Italy.
A Great Divide: Regulation of Mitotic Transitions
Rosella Visintin’s scientific career began with a deception. Not a little white lie, but a whopper. Determined to do undergraduate research in genetics at the University of Milan, Italy, she met all the entry requirements except one: command of the English language.
“I thought, why should I not go there just because I don’t know English? I can learn it. So I lied and went there without knowing a word,” Visintin recalls. It wasn’t that she had no regard for rules; she just refused to be deterred. That bold attitude was an early indication of the persistence that Visintin, now a group leader at the European Institute Foundation of Oncology in Milan, applies to every scientific problem she encounters.
She learned about hard work and perseverance from her mother, a seamstress, and father, a maintenance man for a pharmaceutical company. “They taught me respect for every kind of work, from the most humble to the most sophisticated,” Visintin says. Now she tries to impart to her students a similar appreciation for the nitty-gritty parts of research.
“Luck does play a part, but really, science is hard work,” she says. “I say, ‘Don’t be disappointed to do what may not be the coolest experiment, because if you don’t do it, you’re never going to get to the coolest experiment.’”
Visintin’s efforts and insights have led to significant discoveries about regulation of the cell cycle—the process by which cells grow, replicate their genetic material, and divide. All living organisms rely on this process for growth, repair, and reproduction, and when it goes awry, the consequences are serious. Cancer, for example, results from errors in cell division.
Like a ballet, with dancers entering and exiting the stage and executing specific steps in the proper sequence at the right time and place, the cell-division cycle is an ordered series of events carried out by a cast of molecular players that must act at the right time in the right place. Proteins called kinases act as choreographers, controlling the activity by tagging particular molecules with phosphate. “When a molecule is tagged, it does something it would not do without the tag, such as changing positions in the cell or entering a different pathway,” Visintin explains.
As a postdoctoral researcher in the lab of HHMI investigator Angelika Amon at the Whitehead Institute and at the MIT Center for Cancer Research, Visintin found that specific tag-removing proteins release cells from the cell division process by undoing the work of kinases. A key contribution was identifying a phosphate-removing protein called Cdc14 in yeast and finding that the protein’s activity is controlled by its location in the cell. When it’s not needed, Cdc14 is kept offstage in a dense sphere called the nucleolus. On cue, it’s released and moves about freely to do its job. Since then, phosphate tag-removing proteins (called phosphatases) have been found and studied in organisms from yeast to humans.
Kinases don’t necessarily leave the stage when phosphatases appear; the two sets of choreographers compete for rights in the cell division dance. Visintin, herself a one-time ballet student, wants to understand more about the interplay between the antagonistic directors. “Different sites in the cell may have different ratios of the two, which determines which one is in control,” she says.
Another process she wants to explore is the separation of duplicated chromosomes— known as sister chromatids—an event that must occur during cell division so that each resulting cell receives one and only one copy of each chromosome.
“The two sisters are tightly held together by a glue called cohesin until the right conditions are met and everything is ready to go,” Visintin explains. Then a signal is sent, the glue is removed, and the chromatids separate. Scientists have thought that cleaving cohesin is enough to start the separation process. But Visintin has hints—from a mutant yeast strain that lacks cohesin yet can’t achieve chromatid segregation—that other factors are at play. In particular, she’s interested in the role of the spindle, the structure along which chromatids are pulled apart.
Spindle, chromatids, phosphatases, kinases—filling in the blanks in the cell-division cycle story will take some serious effort. It should come as no surprise that the prospect doesn’t worry Visintin one bit.