At that same meeting over the past weekend, I heard Tim Mitchison give an interesting talk about mitosis and pharmacogenetics. For any of you who don't know, Tim's lab has been at the fore front of analyzing how the mitotic spindle operates. Tim was the first to visualize microtubules, the major constituents of the spindle, in a live cell. In his seminar, he led us on a tour of 20 years of thought about mitosis. In the past 5 years Tim had been involved in developing drugs that would inhibit mitosis and thus be used as a treatment against cancer. He was responsible for setting up the ICCB, and this led to the development of monastrol and other inhibitors of Eg5, a kinesin involved with spindle organization. Overall though the major cancer cures have come from inhibitors of intracellular signalling pathways and by mucking up the microtubules themselves.
So why is this? How come there is all this research into the cell cycle yet so few anti-mitotic chemotherapy drugs?
Tim had some ideas.
- Inhibiting microtubules may stimulate additional cellular events such as apoptosis (regulative cell death). Perhaps this extra signalling explains why drugs that target the microtubule cytoskeleton are the most effective of the chemotherapeutic drugs that target mitosis.
- Perhaps we are too focused on the most conserved portions of the cell cycle. Inevitably when you inhibit cell division throughout the body you nuke your white blood cells and other highly proliferative tissues like the lining of the gut. Microtubule drugs are especially bad as they damage your nervous system.
- Perhaps we are overlooking specialized targets. There has been a big push in biology to focus on the most conserved parts of the cellular machinery - parts so essential that they are found in the yeast cell cycle as well. By hitting those components, anti-mitotic drugs hit the body too hard, nuking every cell in sight. If we found proteins important for mitosis in Hela cells but not CHO cells that would be a good start. And that brings up a related issue, why are some cell types susceptible to cancer? In fact why are epithelial cells generally prone to cancer while fibroblasts aren't? Are there differences between the mechanism, of mitosis between cell types? By investigating how various cell types differ in how they divide, we may discover quite specific targets for cancer therapy. By focusing on how mitosis differs between species, we may target more of the peripheral mitotic machinery that will spare other cellular processes.
Quite an interesting take on the whole topic.
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It is a nice point of view on mitosis. On the side, I though Shinya Inou� was the first to observe microtubules live, using polarized cell microscopy.
Shinya imaged the spindle with polarized light and infered that it was made of parallel microtubules, but he didn't visualize individual microtubules. Tim was the first to label tubulin and inject it into cells and see dynamic instability of individual tubes.
I have heard that the mitotic spindle doesn't pull chromosomes apart, but pushes them. A researcher told me that cutting the microtubules with a laser caused the opposing chromosomes to move back to the centrosome. Can you verify this?
JW,
There is a bit of pushing and pulling. When the chromosomes are lining up in metaphase, microtubules are growing from the plus end and at the same time shrinking at their minus end, so the spindle is extremely dynamic and causes these simultaneous pushing and pulling forces. In addition, kinetochore microtubules respond to tension in certain systems, a lack of tension causes the chromosome to be still at the metaphase plate, pulling on one end of the chromosome causes pulling on the other end again keeping the chromosome in the center of the cell. During anaphase chromosomes are definitely being pulled to the poles by shrinking microtubules.