Biology 466 Unsolved Problems Fall 2011
Plus several related questions: * Such as whether DNA polymerase copies base sequences faster?
* Is increase in volume per cell part of what we mean by "growth"? * Which stages of the cell cycle are speeded up? G1, S, G2, or M? Maybe just one; maybe all? [Incidentally, embryos of many species, sea urchins, frogs, flies etc. but not mammals, "turn off" their normal checkpoint controls during the first 10 or so cell divisions. This allows them to divide as rapidly as once or twice and hour, or even quicker. This kind of embryonic growth doesn't include cells getting bigger, let us notice.
Cell cycle times of 15 hours to 25 hours are normal for tissue culture cells ("fibroblasts" and various epithelial cells) whether they are cancerous or not. Nerve cells never have another S period after forming an axon (It was worth a paper in Science when somebody managed to stimulate a nerve cell with an axon to copy its DNA! That is a measure off how unusual it is for a nerve to make DNA).
Speeds of cell cycles can be determined several ways: 1) Watching time lapse videos and films. 2) Using radioactive precursors of DNA. 3) Accumulating mitotic spindles, using colchicine or other inhibitors of microtubules (you could also use vinblastine, for example). Suppose 10% of a population of tissue culture cells stopped during mitosis, at the end of a 5 hour exposure to colchicine: What could you conclude about total cell cycle time, in the absence of drug? Suppose 10% of nuclei became labeled with radioactive DNA precursor (tritiated thymidine) as a result of five hours of exposure to the precursor. What could you conclude from that? 4) Flow cytometry machines (expensive, but quick & reliable, alternative to #2 above)
Suppose that a certain kind of cancer cell has a shorter G1 period, with the S, G2 and M periods being the same as in normal cells; then should we expect those cells to be more sensitive (=killed) to drugs that interfere with DNA synthesis? What about drugs that block mitotic spindle formation?
Ask yourself if cells that have a longer than usual S period, as a % of a cell cycle of the same total time, will seem to be growing faster. What about cells that spend a longer % of their cell cycle in mitosis?
What if some kind of cancer cell had a shorter S period, than normal? Then should we treat it with cyclophosphamide and daunorubicin? But not treat it with vincristine or with taxol?
Imagine that S and M periods have the normal durations in a certain kind of cancer cell, but the G1 and/or the G2 periods are much quicker; then would you expect any of the 4 drugs listed above to be able to hurt that kind of cancer cell (more than they hurt normal cells)?
Would you expect that biopsy cells would be grown in culture, and the durations of their G1, S, G2, and M periods would be measured, in order to decide which kind of drug to use? Spindle poisons (= tubulin poisons, like vincristine) versus DNA synthesis poisons, like cyclophosphamide and topoisomerase inhibitors? My point is that neither diagnosis nor treatment of human or animal cancers includes any effort to measure the speeds of cell growth, cell cycles, or mitoses. Speeds of growth are not measured nor compared with growth rates of patients' normal cells. The idea that cancer cells grow faster is frequently claimed, but seldom or never tested. If it were true, then chemotherapy methods could be adjusted according to which part of the cell cycle was found to be abnormal. Nobody has even tried to do such a thing, as far as I have been able to find out.
On the other hand, the following set of three related facts do fit the idea of cancer cells growing faster: #1) Many chemotherapy drugs are especially toxic to faster growing cells (and often designed that way) #2) The faster-growing forms of cancer are usually the most curable by these chemotherapy drugs. #3) The side effects of these particular drugs are worst for faster-growing normal cell types, of the skin and hair, of hemopoietic bone marrow cells, and stem cells that continually replace intestinal lining. An alternative way to interpret these facts is that apoptotic cell death is caused when cells continue past cell cycle checkpoints despite damage to their DNA or their mitotic spindle. Suppose that a certain mutation caused faster cell cycles: would that make it an oncogene? Mutations that weaken cell cycle checkpoint controls definitely are considered oncogenes. But what if a gene increased growth during G1 or G2, so cells enlarged sooner?
In the technique for making monoclonal antibodies, fast-growing "myeloma cells" are fused with B-lymphocytes, and the fused cells become fast-growing, antibody-secreting "hybridoma" cells.
HeLa tissue culture cells "took over" cultures of thousands of other kinds of cells, probably/mostly
by multiplying faster than the original cells of cultures that they contaminated. Alternatively/partly
they took over by continuing to grow longer in "used up" tissue culture media. Managing to go through a few more cell cycles per time of replacement of tissue culture media would be as effective as faster growth in taking over a culture. Many people would loosely call that growing "faster". Three divisions in three days versus two divisions in three days! Is that faster? Or is it only decreased "control"?
Just now, I searched for specific information about cancer cell growth rates in those two large, heavy books on cancer. One chapter mentions that some of the more treatable, fast growing cancers have cell doubling times less than a month. A MONTH said I!? Others kinds of cancers considered rather fast-growing had doubling times of 2 to 3 months. The first chapter's first table of data compares "labeling index percentages (% of cell containing radioactive DNA, after short pulse of labeled thymidine) as high as 75% for non cancerous "myeloblasts", from which they estimate cell doubling times as short as 0.7 days. That's about as fast as what you see in videos of tissue culture cells. For "High grade" lymphomas, they report labeling indexes of 19-29%, from which the three authors (one of whom, I just noticed, is somebody I admire tremendously!) estimate "doubling times" of 2 to 3 days. That is much faster than normal lymphocytes. But it is also much faster than slower-growing lymphoma cells. Their method indicates normal intestinal "crypt cells" duplicate themselves in 1 to 2 days.
Maybe we should offer a free pizza to whoever can find a scientific paper with actual data about some kind of cancer whose cell cycle is shorter than any normal kind of cell in the body. In none of the biopsies done on me were there attempts to measure the growth rates or cell cycle times. If it were really true that cancer cells grow faster, then what's the evidence? My belief is that there may actually be true examples of faster growth by cancer cells. But I believe much more strongly that many more studies ought to have been done, so that we would know, for sure. People have been so sure, they haven't bothered to do critical experiments to find out.
When you make a systematic study of unsolved problems in Biology, again and again, you find one or two or three beliefs (per subject) that "everyone knows", but about which there turns out to be almost no data, neither pro nor con. The phenomenon deserves a name, like "urban folklore".
We should have a contest to invent a good, catchy name for such beliefs.
Unconfirmed certainty? Dataless knowledge? Too sure to test? Invincibly plausible guess?
Everybody-knows-ism? Maybe Latin or Greek has a good word or phrase?
Or a German pun would be to say that such and such a fact was proven true by Alice Weiss.
Todo el mundo lo sabe.
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