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December 17, 2001

High-tech movies show vivid details of living cells

Images of the cell cycle show effects of genetic mutations and of cancer-fighting drugs

By Tim Stephens

Using an imaging technique that records movies of microscopic processes inside living cells, scientists are learning new information about how mutations in certain genes cause cancer and how cancer-fighting drugs work. The procedure also shows promise as a way to rapidly screen compounds for potential use as anticancer drugs, said William Sullivan, professor of molecular, cell, and developmental biology.

Successive phases of cell division are shown here in three sets of images. Tubulin (a protein that plays a key role in cell division) is highlighted in the top row and DNA (chromosomes) in the middle row; in the bottom row, tubulin is red and DNA is green. Photo: Kristina Yu
Sullivan developed the procedure as part of his research on the cell cycle--the process of cell growth and division--and how it is regulated. Mutations in genes that regulate the cell cycle can cause cancer, which is essentially unregulated cell proliferation. Drugs used in cancer chemotherapy interfere with the progression of the cell cycle in various ways.

Using advanced microscopy and fluorescent labeling techniques, Sullivan is able to observe chromosomes and other key structures within cells as they progress through the various phases of the cell cycle. Movies of normal cells show bright green chromosomes lining up and separating neatly into two daughter cells, guided by the glowing red filaments of a structure called the mitotic spindle. When something disrupts the cell cycle, whether it is a mutation or an anticancer drug, Sullivan's detailed movies of living cells show exactly what part of the cycle has been affected and how.

"These movies are a great tool. We can learn so much by seeing what happens in real time in living cells," he said.

[Images and movies from Sullivan's research can be seen on his web site,]

Sullivan found the ideal cells for this type of analysis in the early embryo of the fruit fly, Drosophila melanogaster, commonly used in genetic research. Immediately after fertilization, the cells of the embryo go through a series of rapid, synchronous divisions. During this stage, thousands of cells in a single layer (convenient for microscopic examination) are all dividing at the same time and completing a cell cycle every 12 minutes. Sullivan can simply put a live fruit fly embryo under the microscope and peer into its cells as they go through repeated cycles of cell division.

"It would be a lot harder to do this with human cancer cells growing in tissue culture, because those cells only replicate every 24 hours," Sullivan said.

Human genes involved in cell-cycle regulation and cancer have close counterparts in the fly, so results from the embryo assay are directly relevant to cancer research. Initially, Sullivan used movies of cell division in fly embryos to analyze the effects of mutations in cell-cycle genes. Impressed by the results, he began doing similar studies with drugs used in cancer chemotherapy.

"We can see in unprecedented detail the effects of each drug on the cell cycle," Sullivan said. "Even for well-characterized drugs, we are obtaining new insights into their mechanisms of action."

One drug, for example, was found to compromise a particular cell-cycle checkpoint. Checkpoints maintain the integrity of cell division by ensuring that each step in the cell cycle is completed before the next step begins. A checkpoint may halt the cell cycle so that repair processes can operate before errors are passed on to daughter cells. Sullivan found that the drug, which belongs to a class of drugs called topoisomerase inhibitors, disrupts a checkpoint that makes sure all of a cell's DNA has replicated to produce two copies of each chromosome, one for each daughter cell. The movie showed cells prematurely entering the phase in which the chromosomes separate (called metaphase).

"The combination of timing data and morphological information is very useful," Sullivan said. "We know that it takes eight minutes to replicate the DNA, but we see the cell going into metaphase at six minutes. The chromosomes just break into fragments because they are still stuck together when the cell divides."

Sullivan plans to run the assay on all of the roughly 80 drugs commonly used in cancer chemotherapy and compile the results in a database. He is testing drugs in normal flies as well as flies that carry mutations associated with cancer.

"We'll have a movie of each drug that shows how it affects the cell cycle and how it interacts with certain mutations," he said.

Sullivan also plans to team up with other UCSC researchers to screen natural and synthetic compounds for their effects on the cell cycle.

"We want to identify compounds that don't kill normal cells but affect cells with mutations typically found in cancer," he said. "The idea is to tailor drug therapies to affect the genetic mutations that occur in specific cancers."


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