History and The Cell Cycle, Cellular Growth, and Cancer
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.