Wednesday, May 10, 2006

Reversing the cell division cycle

Most eukaryotic cells are "diploid", which means that each cell contains two copies of most of the chromosomes in the total genome (excepting the sex chromosomes, which in mammals are known as X and Y). The two copies of each chromosome are not entirely identical, though each contains the same genes. The difference is due to isolated variations that may occur within genes or outside genes in the non-coding "junk" DNA of a chromosome.

Humans, for example, have 22 paired chromosomes (besides the sex chromosomes). Both chromosomes in each pair have the same genes, but slight differences exist since in each pair is an almost exact copy of one chromosome from each of the parents. (The copies are not quite exact, due to mutations that may have occurred since the paternal sperm fertilized the maternal egg.)

It is important that every daughter cell that results from cell division continues to have both variants of each chromosome. This guarantees that every cell in the body continues to have the same genome, in which every gene is represented by a copy from each parent. For example, if 1 and 1* designate the two copies of chromosome number 1, then both daughter cells should have a 1 and a 1*, rather than two 1s in one daughter and two 1*s in the other.

Of course, this only applies to organisms (usually multicellular) which undergo sexual reproduction involving the fusion of an egg and a sperm. Cells of such an organism are "eukaryotic", which means that they have a nucleus and a genome consisting of several chromosomes which have a fairly elaborate internal structure.

It should not come as a surprise that the process of cell division required in order to keep all the genetic information straight is fairly complex. The overall cell division process is referred to as the "cell cycle". Sometimes the whole process is referred to loosely as "mitosis", but cell biologists normally reserve that term for the final phase of the cycle, in which all parts of the dividing cell are apportioned between each of the new daughter cells.

There are three other phases of the cycle before mitosis. Omitting most of the details, all that needs to be said is that it is in the second phase when the DNA making up the chromosomes is actually duplicated. This is a fascinating process in itself, but not relevant here. All you need to know is that after the DNA has been duplicated, each and every chromosome consists of two identical copies (unless an undetected copying error occurred). These duplicate copies are joined together at a point in the middle called a "centromere", and each copy in the pair is called a "chromatid". So at this point, there are actually four copies of each chromosome type (other than sex chromosomes) -- two copies from each of the organism's parents.

Later, in the mitosis phase, each pair of chromatids will be separated in such a way that each daughter cell inherits half of every pair of (identical) chromatids. All the complexity of the process lies in the mechanics of how this is accomplished. Basically, what happens is that all the chromatid pairs migrate to a plane roughly in the middle of the cell. At the same time, two spots known as "centrosomes" form on the cell membrane on opposite sides of the central plane. From each centrosome a network of threadlike "microtubules" is constructed. Eventually, every chromatid is attached to just one of the two centrosomes by a sort of loosely woven rope of microtubules. Once all of this is in place, the connection is severed between chromatids in each pair, and every chromatid begins to "climb" up its connection towards the centrosome it's attached to. Finally, the central part of the cell contracts, new nuclear envelopes form around the chromatids in each half, and at the end the two halves separate. And then the cycle begins again in its initial phase.

Given all this complexity -- most of whose details have been omitted -- I found it quite interesting, and surprising, that new research indicates this whole process can be reversed! This doesn't seem to happen naturally, as far as we know, but it can be made to happen by manipulating some of the proteins (known as "cyclins" and "kinases") that regulate the cell cycle.

Here's the press release that announces the pubication in Nature of the research: Rewind, please: OMRF scientist reverses process of cell division. Unfortunately, the press release itself is really lame. It explains almost nothing about the actual research -- so if one is at all curious about what is actually meant by "reversing" the cell division process, one is quite disappointed.

The research article itself, whose lead author is Gary Gorbsky of the Oklahoma Medical Research Foundation, can be found here. Unfortunately, unless you have a subscription to Nature (or are willing to pay $30 for the privilege of having one week's access to the article), you won't be allowed to see it. But at least you can view the abstract here.

Even that won't be too helpful unless you're really up on your cell biology. So I'll try to explain in something a bit closer to English what the research is actually about.

As noted above, the transition between phases of the cell cycle is regulated by proteins called "cyclins" and "kinases". Within each phase, the appropriate genes get switched on to bring about whatever activity is to occur in that phase. In particular, the mitosis phase is kicked off by the appearance of a "cyclin-dependent kinase" called Cdk1 along with a cyclin molecule called, simply, cyclin B. Cdk1 is an enzyme that catalyzes the attachment of phosphate groups to other molecules. But it's active only when it has a cyclin attached, in this case cyclin B.

The cyclin molecules are not as robust as the kinases, which is a good thing, because it is their eventual breakdown, after all the work is done, that deactivates the kinase and allows a new phase of the cycle to commence.

What the research found is this: After the mitosis phase has ended ("mitotic exit"), but before the two new cells actually separate, the process can be returned to the middle of the mitotic phase by manipulating Cdk1 and cyclin B. What you do is block the degradation of cyclin B but use an inhibitor to disable Cdk1. Mitotic exit still occurs. But if you quickly remove the Cdk1 inhibitor, the process reverses. The membrane between the new cells reopens, the new nuclear envelopes break down, the microtubules reappear, and the chromosomes move back to the middle of the cell. Got that? The bottom line is that the degradation process of cyclin B provides directionality for the later part of the mitosis phase.

Well, all in all, it's a really fascinating bit of bio-hacking. Is this somehow, you know, useful in any way? Well, at least it's very interesting new knowledge about how fundamental cellular processes work. If we learn how to control the processes, we may figure out how to intervene in disease conditions when cells malfunction -- as in cancer, for instance. After all, cancer involves runaway cell division. If you can reverse the whole division process -- selectively, where it should not be happening -- you may have just found a cure for cancer.

See also:
Gary Gorbsky home page
Gorsky Lab Home Page
Cell division rewinds

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Anonymous Organic Chemistry said...

As you stated at the end of the post, selectivity is obviously the key. One way that selectivity has been acheived in this type of work is through different cell-surface carbohydrates. Maybe selectivity thru cell-surface carbohydrates, following by a "wonder drug" employing the "reversal" methodology would be the winner.

1/25/2007 06:05:00 AM  

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