Chapter 4

At first glance, the orderly progression of the cell through the phases of the cell cycle may seem perfectly straightforward. When building a house, the walls aren't erected until after the foundation has been laid. Likewise, in the cell, mitosis doesn't begin until after the genetic material has been copied. Otherwise, the daughter cells would end up with less than a complete set of chromosomes and would probably die. So in the cell cycle, just as in housebuilding, certain steps need to precede others in an orderly fashion for the process to work.

How does the cell "know" when a step has been completed and it's time to move on to the next? The answer is that the cell has several molecular "inspectors" stationed at intervals—called checkpoints—throughout the cell cycle. These cellular inspectors function much like building inspectors do: If a step has been completed to their satisfaction, they give the OK to move forward. If not, they halt progress until the cellular construction workers finish the task. There are three major checkpoints in the cell cycle: one between G₁ and S phase, one between G₂ and mitosis, and one during mitosis itself.

The concept of checkpoints in the cell cycle was first introduced by Ted Weinert of the University of Arizona in Tucson, and Leland Hartwell of the Fred Hutchinson Cancer Research Center in Seattle, Washington. In experiments with yeast cells, Weinert and Hartwell showed that a protein called Rad9 is part of a cell cycle checkpoint. Normal cells will stop and repair any damage to their DNA before embarking upon mitosis. Cells that lack Rad9, however, ignore the damage and proceed through mitosis, with catastrophic consequences—having inherited damaged DNA, the daughter cells invariably die. Since these discoveries were made, other checkpoint genes have been identified in many kinds of cells, including human cells.

Hartwell has identified more than 100 genes that help control the cell cycle, and in recognition of the importance of these discoveries, he shared the Nobel Prize in physiology or medicine in 2001.

Your body carefully controls which cells divide and when they do so by using molecular stop and go signals. For example, injured cells at the site of a wound send go signals to the surrounding skin cells, which respond by growing and dividing and eventually sealing over the wound. Conversely, stop signals are generated when a cell finds itself in a nutrient-poor environment. Sometimes, however, go signals are produced when they shouldn't be, or stop signals aren't sent or heeded. Both scenarios can result in uncontrolled cell division and cancer. Mitosis then becomes a weapon turned against the body, spurring the growth of invasive tumors.

Fortunately, it takes more than one mistaken stop or go signal for a cell to become cancerous. Because our bodies are typically quite good at protecting their essential systems, it usually requires a one-two punch for healthy cells to turn malignant. The punches come in the form of errors, or mutations, in DNA that damage a gene and result in the production of a faulty protein. Sunlight, X rays and other radiation, toxins such as those found in cigarette smoke and air pollution, and some viruses can cause such mutations. People also can inherit mutations from their parents, which explains why some families have higher rates of certain cancers: The first punch is delivered at conception. Subsequent mutations can then push a cell down the path toward becoming cancerous.

Ironically, mitosis itself can cause mutations too, because each time a cell's DNA is copied, errors are made. (Fortunately, almost all of these errors are corrected by our extremely efficient DNA repair systems.) So there's an inherent tradeoff in mitosis: It allows us to grow to maturity and keeps us healthy, but it's also the source of potentially damaging DNA mutations. We'll come back to the link between cell division and DNA damage when we talk about aging in the next chapter.

If mitosis is a show, then chromosomes are the stars. The main plot line is the even distribution of stars into two groups by the time the curtain goes down. But the stars play an unusually passive role. A director called the mitotic spindle moves them from here to there on the cellular stage. The mitotic spindle—a football-shaped array of fibers made of microtubules and associated proteins—forms at the beginning of mitosis between opposite ends, or poles, of the cell.

The chromosomes (blue) become attached to the spindle fibers (green) early in mitosis. The spindle is then able to move chromosomes through the various phases of mitosis.

How spindle fibers move chromosomes has captivated scientists for decades, and yet the answer remains elusive. Conly Rieder, a cell biologist at the Wadsworth Center in Albany, New York, is investigating this challenging question. Some scientists believe that motor proteins act like cellular buses, conveying chromosomes along the fibers. Others, including Rieder, favor the idea that microtubules shrink or grow at their ends to reel in or cast out chromosomes. Still other scientists believe that the answer will come from combining both views.

The potential applications of this molecular detective work are significant. When the spindle makes mistakes, chromosomes can end up in the wrong place, which may lead to cells with abnormal numbers of chromosomes. This, in turn, can cause serious problems, such as Down syndrome, cancer, or miscarriage, which, in 35 percent of cases is associated with cells carrying an atypical amount of genetic material.

Men produce sperm continuously from puberty onward, and the formation of a sperm takes about a week. The situation is quite different in women. Baby girls are born with a certain number of "pre-egg" cells that are arrested at an early stage of meiosis. In fact, the pre-egg cell does not complete meiosis until after fertilization has occurred. Fertilization itself triggers the culmination of the process. This means that meiosis in women typically takes decades and can take as long as 40 to 50 years!

Scientists have long suspected that this extended meiosis in women is responsible for certain genetic disorders in their children. The pre-egg cells have years in which to accumulate damaging mutations that may cause errors in the remaining steps of meiosis. For example, the risk of Down syndrome, a common cause of mental retardation, increases in the babies of older mothers.

The syndrome occurs when the chromosome 21 pair fails to separate during meiosis and both copies of the chromosome end up in a single egg cell. Subsequent fertilization by a sperm means that the resulting cell has three copies of chromosome 21 rather than the standard two. No one knows exactly how or why the chromosomes fail to separate, and the question has been difficult to answer because of the lack of a suitable animal model in which to study the disorder.

Now, Sharon Bickel, a molecular biologist at Dartmouth College in Hanover, New Hampshire, has developed a method that uses fruit flies to gain insight into this human puzzle. Fruit flies normally produce eggs continuously, but Bickel manipulated their diet in such a way as to suspend egg maturation, allowing the eggs to age. This mimicked the aging of human eggs. Studying the aged fruit fly eggs, Bickel found that the incidence of problems in chromosome separation increased, just as it does in older women. Her work also indicated that a backup genetic system that helps to ensure proper chromosome separation and distribution deteriorates as fruit fly eggs age. No one yet knows if the same backup system exists in humans or if the same mistakes seen in the flies account for the increased risk of Down syndrome in the babies of older mothers. But the fruit fly model system will allow Bickel and others to investigate these important questions.