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CELL BIOLOGY Drug Stops Motor Protein, Shines Light on Cell Division Myosin's Leading Role Makes Precision Inhibitor Powerful New Tool for Research Scientists studying how cells know when and where to divide have a new tool to study the final, fast stages of cell division. The first experiments using this tool reveal some of the molecular conversation that helps a cell tightly choreograph the time and place of pinching into two cells. Blocked exit. A normal frog XTC cell (top left) has duplicated its DNA and separated by mitosis into two sets of chromosomes, each destined to go into a different daughter cell. Then, in tightly choreographed cytokinesis (middle left), microtubules tell the cell when and where to set the furrow and contract, cleaving one cell into two daughter cells (bottom left). Some blebbing is evident. Under the influence of blebbistatin, the cell goes through the mechanics of cell division (top and middle right) without myosin to time and power the final cleavage, leaving one cell with twice the normal amount of DNA (bottom right). The images are taken from Quicktime movies of a cell dividing normally and a cell dividing under the influence of blebbistatin. (Images courtesy of Aaron Straight) In the March 14 Science, researchers from HMS and colleagues report the discovery of a small compound, called blebbistatin, that quickly and reversibly blocks the final cleavage motion after cells have duplicated and separated their chromosomes. Blebbistatin works by interfering only with myosin II, a motor protein essential for cells to contract and move, while preserving other molecules and functions in cell division, said HMS postdoctoral fellow Aaron Straight, first author of the paper. Blebbistatin stops myosin II from splitting a cell undergoing division, arresting one component of a complex series of events. "What's great about blebbistatin is that it appears to be functionally specific." --Bob Adelstein "What's great about blebbistatin is that it appears to be functionally specific," said Bob Adelstein, head of the molecular cardiology laboratory at the National Heart, Lung, and Blood Institute, who has reported developing a knockout mouse that lacks cardiac nonmuscle myosin II; it has a similar defect in cytokinesis but other problems in the cell cycle, as well. "Other inhibitors can screw up the cell. So can dropping out myosin genetically. Blebbistatin is like using a scalpel to dissect myosin out of this part of the cell cycle." Small Molecule, Big News Blebbistatin was discovered by using a myosin assay to screen 17,000 small molecules from the chemical library of the HMS Institute of Chemistry and Cell Biology, codirected by Timothy Mitchison, the Hasib Sabbagh professor of cell biology and co-author of the paper. Aaron Straight, Tim Mitchison (l to r), and colleagues invented a small molecule with scalpel-like precision to block the motor protein myosin II and used it to dissect some of the final stages of cell division. (Photo by Graham Ramsay) Identification of the compound was not as straightforward as it first appeared. When researchers ordered a purified compound for further tests, they found it was totally inactive for blocking myosin II. It took another year to unravel the chemistry that converted the original sample and then to make the new small molecule in the lab. The researchers subcontracted manufacture of blebbistatin to an outside company, in anticipation of high demand for the new drug. The drug went nameless for some time. As experiments proceeded on cells, a whiteboard outside Straight's lab filled up with suggestions--myostoppin, contracontractin, cleavostatin, furrowstatin, old yeller (it was yellow), and even Baywatchostatin (since it stops cleavage). The name "blebbistatin" was finally chosen based on early experiments on HeLa cells, a cancer cell line, in which it inhibited blebbing, a mysterious myosin-related process of a raspberrylike bubbling on the cell membrane, associated with apoptosis and cytokinesis. Protein Tasks Using blebbistatin, Straight and colleagues discovered more details about the action of myosin in cytokinesis. "A complex network of signaling from microtubules to the cell membrane tells the cell both when and where to divide," Straight said. In one of two main findings, they showed for the first time in mammalian cells that a cell uses the same mechanism to finish division, ubiquitin-mediated proteolysis, as it uses to start it, which had been shown earlier in yeast. Specifically, when they blocked the proteolysis machinery--the proteasome, which destroys proteins as a necessary step in many cell functions--the cell was unable to complete cell division. In the other finding, the researchers identified a few of the molecular details that the microtubules use to signal the time and location of cell cleavage after they pull the duplicated chromosomes apart. The signals between the microtubules and the cell membrane diverge into two pathways, one that signals myosin and a second unknown pathway that positions another protein, anillin, needed for the final stage of cell division. "Blebbistatin allowed them to distinguish among steps that are unrelated to myosin II, steps that put myosin II in the right place, and steps that require myosin II to work normally," said Henry Bourne, a professor of medicine and pharmacology at the University of California, San Francisco. "Consequently, now we know precisely when and where the action of myosin is required in the complex molecular dance necessary to divide a cell into two." Bourne is one of dozens of scientists who see vast potential in blebbistatin as a research tool. "The paper is significant in a more general way, as a prime example of how we can use drugs to dissect complex, rapid biological processes," said Bourne, who is using blebbistatin to dissect the role of myosin II in aspects of white blood cell activity essential for fighting infection and tissue injury. --Carol Cruzan Morton