TECHNOLOGY FOR CHANGE

3D Dataviz Key to Next-Gen Bio Research

John Jainschigg | Date: 06-28-10 | Comments

3D cell cultures show much promise for drug candidate evaluation and uncovering new mechanisms that can be targeted for medical treatment.

Historically and of necessity, much cell biology has had a two-dimensional bias. For culturing cells and observing their behavior en masse, biologists have long used the classic Petri dish� simple, cheap and space-saving�filled with a flat substrate of semiliquid/gel culture media. And as a result, many standard methods for evaluating, for example, the efficacy of drug therapies against the spread of cancer involve charting the way drug candidates affect migration of cells across a flat substrate.

Recent research by biomedical engineers at Johns Hopkins, published in the June issue of Nature Cell Biology, however, suggests that such 2D techniques may be giving a false picture�leading to misinterpretation of or failure to identify cell migration mechanisms that work differently in vivo than on flat substrates.

The team from Johns Hopkins Engineering and Oncology Center, headed by principal investigator Denis Wirtz and lead study author, Ph.D. candidate Stephanie Fraley, explored how so-called "focal adhesions"�proteins that let cells stick to a flat surface, temporarily, limiting cell migration�work when cells are cultured on a 2D substrate, or within a 3D matrix.

What they discovered was surprising: On 2D substrates, focal adhesions form easily and may last for several minutes. But, says Fraley, the shape of cells in 2D and the importance of focal adhesions limiting movement are "merely artifacts of their environment." In 3D matrices, says Wirtz, the same cells assume a distinctly different shape, "focal adhesions disappear and the role of adhesion proteins in regulating cell motility becomes different." The researchers discovered that cells moving in 3D environments make only very brief and short-lived contacts with collagen fibers surrounding them. Such loss of adhesion and enhanced cell movement are hallmarks of the metastatic process by which cancers spread throughout the body.

Another striking observation made by the investigators involved zyxin�a protein that also seems to help govern cell migration, and whose expression is misregulated in many cancers. In a 3D matrix, cells expressing zyxin move in a random way. But when the gene for zyxin is disabled, the cells begin traveling in more linear fashion, far from their point of origin. Neither behavior is manifest on 2D substrates.

Such dimensionally mediated differences in function, the researchers say, may help explain why results from laboratory and clinical studies sometimes differ�why a drug that shows huge promise in the laboratory fails to work as expected in live animal or human subjects. Wirtz suggests that 3D cell cultures are bound to become more important in drug candidate evaluation, and that 3D techniques for cell culture and observation will help elucidate new mechanisms that can be targeted for treatment.