Study Guide

The Cell Cycle, Cellular Growth, and Cancer In the Real World

  • Ethics

    You have probably heard about stem cells in the popular media, about how they hold so much promise for human disorders and the ethical concerns about how scientists obtain them, even about how they have become a political issue. All of this information may have you wondering: what's the big deal about stem cells anyway, and how are they different from any other cell in your body?

    Earlier in this module we talked about how the way a given cell divides, and whether or not it can keep on dividing, are important characteristics for categorizing different cell types. Then, what is a stem cell? A stem cell is an unspecialized (undifferentiated) cell, which is capable of dividing and reproducing for long periods of time. Most importantly, stem cells can give rise to, through cell division, other types of specialized (differentiated) cells. It is for this reason that stem cells are hailed for their potential medicinal purposes, such as repairing damaged heart tissue.

    Stem cells divide asymmetrically, meaning that instead of giving rise to two daughter cells with the same fate, stem cells give rise to cells with two different fates. One of the daughter cells takes on a differentiated state, meaning that it becomes a heart cell, for example, while the other daughter cell remains an undifferentiated stem cell capable of dividing again. In this way stem cells are capable of both regenerating tissues and replacing themselves.

    How does the stem cell divide asymmetrically? In some cases, other cells surrounding the stem cell signal to the different daughter cells, which in turn decides which way they'll progress. It is kind of like becoming whom you date, or like those dog owners that suddenly start looking like their dog—creepy. Alternatively, the cells themselves seem to 'know'. During cell division certain proteins, RNA and other biological molecules are relocated to one half of the cell. When the cell divides, these molecules are only contained in one of the daughter cells, meaning that the two daughters have their own unique start on life. Voila. An identity crisis averted (if only it were that easy for us).

    Asymmetric division is actually important for the development of many different species. This importance can be easily viewed in C. elegans, a transparent nematode worm, where scientists have mapped every cell division that comprises the organism. An adult worm has 959 somatic cells plus germ cells. You can even watch all of these divisions at http://www.bio.unc.edu/faculty/goldstein/lab/celdev.mov. Basically, asymmetric divisions in C. elegans helps determine which end of the worm becomes the head, and which end becomes the, well, other end. Yeah, we know: life isn't fair sometimes.

    Another place where asymmetry is important is during oogenesis. The diploid primary oocyte divides asymmetrically during its first meiotic division, giving rise to two cells, one known as the secondary oocyte, which contains most of the cytoplasm from the parent cell, and one known as a polar body. The polar body divides symmetrically during meiosis II, but the secondary oocyte again divides asymmetrically, giving rise to the ovum and another polar body. At the end of meiosis, you end up with one ovum and three much smaller polar bodies, which eventually degenerate. This is different to spermatogenesis, where the primary spermatocyte divides evenly to produce four spermatids at the end of meiosis II, which then mature into functional spermatozoa.

    Now that you understand what stem cells are, you can begin to think about the ethics question. Where do we get stem cells from? We can harvest embryonic stem cells from aborted fetuses, the umbilical cord after a baby's delivery, and from discarded embryos created for in vitro fertilization. Alternatively, scientists have been able to induce some adult cells, which are called induced pluripotent stem cells (iPSCs), to change and so generate other types of stem cells. While there are some questions about the efficiency of iPSCs, iPSCs are generally thought to sidestep the ethical concerns of using stem cells derived from embryos. The potential therapeutic promise of iPSCs is also intriguing because an individual's own cells could be used, therefore bypassing the worry about transplant rejection. Don't forget, though, that adults have their own natural stem cells too, like the ones in bone marrow that produce all of your blood cells. In fact, bone marrow transplants are a type of stem cell transplant, even though most people don't realize it.

    The ethical concerns related to how human stem cells are obtained have significantly impacted on how scientists go about stem cell research. The Bush administration limited federally funded stem cell research to currently existing stem cell lines. In 2009, President Obama repealed the restrictions on stem cell funding guidelines set forth by President Bush. Today these issues are still hot subjects, and will likely remain so for years to come. The debate still rages on – but what do you think?

  • Health

    It is been blamed for the split of Sheryl Crow and Lance Armstrong. Some people call it their biological clock, and for many women in their 30s and 40s, its ticking can be more than a little bit loud. Money doesn't solve everything, and even for women with deep pocketbooks, like Hollywood stars, having a child later in life can be difficult.

    While you probably have heard about a woman's biological clock in reference to the difficulty in having children later in life, you may not understand exactly what it needs to do with cell division. A large player in age related pregnancy difficulties is aneuploidy, a condition where a cell has extra (or missing) copies of a particular chromosome. For women late in their reproductive lives, the possibility of their releasing an aneuploid egg can be 50% or higher. In fact, while the percentage of clinically recognized pregnancies containing an abnormal number of chromosomes is about 2-3% for women in their 20's, the percentage jumps to 30-45% for women in their 40's (Hunt & Hassold, 2008). Aneuploidy is the leading cause of miscarriages, although aneuploidy of some chromosomes is compatible with life. A good example is having an extra copy of all or part of chromosome 21, which leads to Down Syndrome.

    How does aneuploidy happen? Well, we know that most trisomies occur during oogenesis, or the production of a female's eggs, most commonly in meiosis I. We also know that the occurrence of aneuploidy increases with the age of the mother. Why the age correlation? One amazing thing about human meiosis is that the first meiotic division occurs in the fetal ovary, but doesn't finish until ovulation, which can be anywhere from 10-50 years later. While this delay may help explain the age correlation with aneuploidy, it is not the only answer. For example, a surprising number of chromosome 18 trisomies are due to chromosome missegregation in meiosis II, and women who have just started puberty also have a surprisingly high rate of producing aneuploid eggs (Hassold, Hall, & Hunt 2007).

    What could be going wrong in meiosis I that could result in aneuploidy? If you remember back to our In Depth section, homologous chromosomes are held together in meiosis I by the linkages generated through recombination. A common theme concerning trisomy 21 cases is that the pattern of recombination is altered. If recombination were to fail completely, this would be expected to produce completely random segregation of that chromosome at meiosis I. In other words, there would be a 50% chance that a daughter cell would have an extra copy of the chromosome, and a 50% chance that the cell would be missing that chromosome all together. Current scientific research has also found that mutations in the proteins important for gluing the sister chromatids together and ensuring the pairing of homologous chromosomes—both major events of prophase I—can also lead to chromosome segregation defects (Hassold, Hall, & Hunt 2007).

    Even as scientists make significant strides in understanding what goes wrong in meiotic cell division, any clinical solutions to delay or eliminate age related nondisjunction are far off. For many American women, this is disconcerting, especially given the trend that over the last 30 years women have delayed their first pregnancy by about 3.6 years (Hunt & Hassold, 2008). To compound the issue, some recent research has suggested that environmental factors may also increase the amount of maternal nondisjunction. You may have heard about BPA (bisphenol A) that, after being linked to aneuploidy in model organisms, has been increasingly removed from baby products and water bottles. It brings up the somewhat unfortunate possibility that the female reproductive system is not only captive to its own biological clock, but also to environmental factors.

  • Pop Culture

    In Cloudy with a Chance of Meatballs, water goes into the FLDSMDFR (the Flint Lockwood Diatonic Super Mutating Dynamic Food Replicator) and the contraption spits out clones of meatballs, hamburgers or some other type of delicious food. Fun, yes, but a bit too silly. First of all, water (or H2O) only contains hydrogen and oxygen, and you know by now that food molecules require other elements too, such as carbon and nitrogen. While these scrumptious foods may all be made of cells, you'll probably have guessed by now that the FLDSMDFR is not a way that cells could reproduce themselves. We can all agree that science leads to some cool outcomes, not meatball storms (boo).

    In one Simpsons' clip, Homer evolves from a simple celled organism to a couch potato. Why is this situation deceiving? It implies that if a single celled organism divided enough, the cells could make up a fish, or a reptile, or a monkey. Evolution happens on a long time scale and it is useful to think of common ancestors. Fish didn't become a lizard, but that rather the present day fish and lizards shared a common ancestor a long time ago. The fish and lizards of today are the product of many, many years of evolution and countless cell division events.

    In the Twilight movie, Edward and Bella make mitosis look easy during biology class when they pick out the different phases of mitosis in an onion root. Wow, finally an example of where Hollywood got science right. It is actually a fun lab, which involves looking at a thin slice of an onion root that has been stained so you can easily see the chromosomes. Find yourself a microscope and some slides and you may even win the golden onion, or at least get an A in your biology class.

  • History

    Ever since the early 1900s scientists have observed cells in the process of dividing, but they didn't understand how they did it (Nurse, Masui, & Hartwell, 1998). In the last 40 years, scientists have made monumental insights into the molecular mechanism of cell cycle control. These insights have had significant impacts on how we view human disorders such as cancer, and the researchers involved have received worldwide recognition. However, the quest to understand cell cycle regulation wasn't always popular with the in-crowd. Yep, even scientists experience peer pressure. Many scientists felt that you had to gain an understanding of the basics of the events of the cell cycle, such as DNA replication, chromosome segregation, and so on, before you could understand how they were regulated. This sentiment was described by Dr. Andrew Murray, who said the common thinking was that "If you couldn't understand the processes that were controlled, you couldn't possibly understand the control circuitry" (Garber, 2008).

    In 2001, the Nobel Prize in physiology and medicine was given to three scientists who made key discoveries as to how the cell cycle is regulated. Each scientist used a unique organism that allowed him to tackle the regulation question. Leland Hartwell and Paul Nurse whom The Sun newspaper has described as the 'David Beckham of science', that may or may not be a good thing, depending on whether or not you are a soccer fan), both conducted their studies in yeast. Paul Nurse used fission yeast (Schizosaccharomyces pombe), a type of yeast that is named after the African beer it is used to produce. Pombe is the Swahili word for beer; and with that, we are back to The Lion King, because hakuna matata is also taken from Swahili. Lee Hartwell used budding yeast, which is used today by bakers and brewers alike.

    Fission yeast grows at its end and then divides in its center by producing a cell plate. Budding yeast, on the other hand, forms a tiny little bud on the parent, or mother cell, which grows until it separates from the mother cell during mitosis. Both yeasts share the advantage that they can be manipulated genetically, meaning that it is relatively easy to delete, replace, or alter their genes. The yeasts also complete their life cycle quickly, making it much easier to look for mutants that failed to regulate their cell cycles correctly. Many of the mutants identified halted at certain steps in the cell cycle, meaning that a normal copy of the gene was required to proceed to the next step. You may be wondering how scientists could study an organism that can't divide, right? Well the scientists used a clever trick: they only used mutants that halted during the cell cycle when grown at particular temperatures. Clever, huh? Using their different mutants, these scientists discovered a network of proteins required for cell cycle progression.

    The third scientist, Tim Hunt, used biochemistry rather than genetics to discover the key protein important for progression of the cell cycle. Working with sea urchin embryos, Hunt and his colleagues discovered the protein cyclin, whose production and degradation governs cell cycle progression. His work, combined with that of studies conducted on frog eggs by other outstanding scientists (Yoshio Masui, Marc Kirschner, and John Gerhart), demonstrated that a clock mechanism existing in the cytoplasm could control cell cycle progression.

    These different studies came together when Lee Hartwell suggested thinking about cell cycle progression in terms of 'checkpoints'. The fundamental idea of the checkpoint model was that a control system in the cell would trip an alarm that would delay the cycle's progress until the previous event was completed. Lee Hartwell and Ted Weinert did a critical experiment to test the checkpoint model. They used yeast mutants that died when their DNA was damaged. Oddly, these mutants did not arrest in the cell cycle after their DNA was damaged. This meant that these cells did not trip the alarm to indicate that their DNA needed repairing, like a normal cell would. They divided anyway, resulting in two daughter cells with damaged DNA. With damaged DNA, these cells could not survive.

    This important experiment led to the identification of important proteins that acted as a 'stop button' or 'checkpoint' to make sure that all DNA is repaired prior to cell division. The same 'stop button' proteins were shown to be important not only in other yeasts, but humans as well. Andrew Murray described the beauty of this experiment. He said: "One of Hartwell's greatest strengths is to do things that, in principle, would have been possible for a fairly long period of time. After they are done you go, 'Oh my lord, that is so simple, why didn't anyone else do that?'" (Garber 2001).

    In the end it all goes to show that doing what is popular isn't always the way to go. For these scientists studying cell cycle progression, the decision to take the road less traveled ended up yielding big payoffs, like a Nobel Prize.

  • Research

    Lee Hartwell, who won the Nobel prize for his work on the cell cycle, also leads the Fred Hutchinson Cancer Center. He recently described what he felt are the most promising directions for cancer research: prevention, early detection and the exploitation of the immune system to fight cancer (Hartwell, 2008).

    Prevention means gaining an understanding of what causes cancer so we can avoid it. The first thing that may come to your mind is cigarettes. The link between cigarette smoke and lung cancer is well established and it is thought to cause mutations in a cell's DNA. Cancer can also be caused by viruses, as is the case with hepatitis B and human papillomavirus. Viruses can alter a cell's DNA or they can alter the cell cycle of the host cell directly, resulting in uncontrolled growth. Currently researchers are trying to gain an understanding of the heritable changes that contribute to a cell's ability to grow uncontrollably and invade other tissues. Cancer progresses from contained growth of the cancer clone to expansion into other tissues. It is the expansion of the cancer into other tissues that becomes the most difficult to treat. This is why early detection is critical for a cancer patient's survival and therefore a hot area for cancer research.

    It has become apparent recently that there is a link between inflammation and cancer, even in cancers that are thought to be caused by environmental factors such as smoking or asbestos. For example, tobacco smoke isn't a mutagen of a cell's DNA, it also triggers chronic inflammation. Some chronic inflammatory disorders, such as irritable bowel syndrome, increase an individual's risk of cancer. The connection between cancer progression and inflammation suggests that suppressing inflammation may be a useful method for preventing cancer. However, in some cases inflammation seems to actually help prevent tumorigenesis (Grivennikov, 2010). This makes sense because inflammation and the immune system is how your body normally fights off infections.

    Usually the immune system won't attack a cancer cell because it thinks it is part of itself, not an invader. The cancer cell is pretty much a wolf in sheep's clothing. It is easy to understand how beneficial it could be if the immune system could recognize and destroy cancer cells. There appears to be a delicate balance existing between a potentially invasive cancer cell and its host immune system that can be tilted towards cancer progression or cancer elimination. Understanding how we can control this biological seesaw phenomenon and tilt it towards both the prevention and treatment of cancer is an active, promising area of cancer research.

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