Scientists have found that mammalian cells are densely "hard-wired" with force-carrying connections that reach all the way from the membrane through the cytoskeleton to the genome. The findings, reported in part in the current issue of the Journal of Cellular Biochemistry, are being hailed as a tour de force that could change how biologists view the cell.
Investigators have traditionally pictured the cell as a bag of biochemical reactions, supported by a passive cytoskeleton of protein fibers. Recent work, however, has hinted that mechanical forces on the cell can affect everything from the way proteins bind to DNA to whether a precancerous cell develops into a full-blown tumor.
Exploring these interactions, a team led by Andrew Maniotis, Donald Ingber, and their collaborators at Harvard Medical School and Children's Hospital in Boston coated 4.5-micrometer beads with fibronectin, a protein that binds only to integrin receptors--cell surface structures moored to the cytoskeleton through the cell membrane. With a manually operated micromanipulation device, Maniotis used a micropipette "like a golf club" to move the beads about 10 micrometers in a second. A video microscope captured almost instantaneous movements of nuclear structures--dense structures called nucleoli suddenly aligning, for example, or gliding toward the edge of the nucleus.
Next, the researchers harpooned structures in the nucleus itself. The scientists drew the structures--nucleoli and chromosomes--out of the breach in the nucleus. Even though chromosomes extracted from dead, fixed cells typically appear isolated, the experiment showed that in the living cells, the chromosomes and nucleoli were always connected by flexible strings. The connections turned out to consist of DNA.
"They have beautifully demonstrated the nature of the physical connection" between a cell's surroundings and genes in the nucleus, says Avri Ben-Ze'ev of the department of molecular cell biology at the Weizmann Institute of Science in Israel. "It would suggest that everything in the nucleus is in fact connected," adds Jeffrey Nickerson of the University of Massachusetts Medical School. "From my point of view, that's remarkable and it's wonderful."
Although it will take further work to learn whether these links really do carry signals to the genes in the nucleus, researchers seem to agree that the results are changing how biologists think about the cell. "For a long time, the mechanical and engineering aspects of cell biology were not appreciated," says David Bensimon, a biophysicist at the École Normale Supérieure in Paris. "This type of experiment ... certainly suggests that there is much to learn about the possible mechanical control of DNA and gene expression and regulation."