NCSA NEWS

Deciphering the amino acid sequence of all-important subcellular structures called microtubules took seven years. Researchers believe that new imaging processes from the Alliance will speed up the next stage of their research.

Microtubules are among the most important structures in living things. They form the skeleton that gives a cell its shape and provide the equivalent of rail transport used to move materials from place to place. And, before a cell divides, hundreds of these flexible tubes assemble, seemingly out of nowhere, at opposite ends to pull the chromosomes apart. Their role in cell division makes them a prime target for cancer-fighting drugs.

However, nobody knew what these microtubules looked like on a molecular level nor how the popular anticancer drug taxol makes the normally flexible microtubules rigid, stopping cell division in its tracks. Nobody knew, that is, until Lawrence Berkeley National Laboratory's biophysicist Kenneth Downing and his colleagues Eva Nogales and Sharon Wolf revealed the 3D structure of the protein from which microtubules are composed. The group constructed a 3D model of the protein, called tubulin, attached to the small taxol molecule, a substance originally found in the bark of the Pacific yew tree. Their findings were published in Nature.

Chemotherapy drugs, taxol included, stop cancerous cells from dividing, but they damage healthy cells as well, causing such side effects as nausea and hair loss. Knowing the 3D structure of tubulin in detail should help scientists exploit the small chemical differences between the tubulin found in normal and cancerous cells. To be effective, a drug molecule must fit into a tubulin molecule like a lock and key. Scientists hope to design drugs that will fit into the shape of tubulin found in cancerous cells but not healthy ones. "That is the dream," says Downing. "And with billions of dollars coming from drugs like taxol, the pharmaceutical industry is certainly interested."

To turn this dream into reality, Downing's team is working with the Alliance's Scientific Instrumentation Application Technologies team to speed up the next phase of the research -- an exploration of why tubulin tends to curl into tiny rings when microtubules disassemble. The team's original work took seven years to complete, in large part because of imaging techniques that one of Downing's colleagues likened to "reading a newspaper in the dark." Downing hopes that new imaging techniques being developed by the Alliance will "shed light" on this process.

Access Online | Posted 3-23-1999