Cell birth, cell asymmetry, and cell death, which lie at the heart of the development, growth, and healing of an organism, are also central to disease processes, most notably cancer. Cell birth is normally carefully restricted to specific locales and times, such as the basal layer of the skin or the root meristem. The liver regenerates when there is injury, but liver cancer is prevented by restricting unnecessary growth at other times.

Some cells persist for the life of the organism, but others, such as blood and intestinal cells, turn over rapidly. Many cells live for a while and are then programmed to die and be replaced by others arising from a stem-cell population. Much attention is now being given to the regulation of stem cells in an effort to understand how self-renewing populations of cells are created and maintained. This research has clear implications for repair of tissue: for example, it could become possible to restore damaged retinas, torn cartilage, degenerating brain tissue, or failing organs. One interesting possibility is that some populations of stem cells with the potential to generate or regenerate tissue are normally eliminated by cell death during later development. If so, finding ways to selectively block the death of these cells could make regeneration more likely. Could the elimination of such cells during mammalian development be the difference between an amphibian that is capable of limb regeneration and a mammal that is not?

Much remains to be learned about the pluripotent state and the transcription factors and other proteins that reprogram differentiated cells to pluripotency. One current model that is under intense investigation relates to the findings that Oct4 is required for differentiation of pluripotent cells to the mesodermal (e.g., muscle) and endodermal (e.g., intestine, liver) states, and that it can be replaced in iPS cell reprogramming cocktails by other transcription factors that promote mesodermal and endodermal fate. Similarly, Sox2 can reprogram cells toward ectodermal lineages (e.g., skin and neural tissues) and can be replaced by other factors that promote ectodermal differentiation. The pluripotent state is thus proposed to be a state of delicate balance between pluripotency factors such as Sox2 and Oct4 that act to promote differentiation along mutually exclusive paths: ectodermal or mesodermal/endodermal differentiation. Under test is the hypothesis that preventing differentiation into the main lineages may itself be sufficient for pluripotency and that slight changes in the levels of these and other transcription factors can promote differentiation.

ES and iPS cells will continue to provide a great deal of information about the regulatory molecules—transcription factors, chromatin- and DNA-modifying enzymes, and noncoding RNAs—and circuits that establish and maintain the pluripotent state and that allow these cells to differentiate down specific developmental lineages. But the main interest in these cells—at least in the public’s mind—is as a source of tissues to replace defective ones. Several neurodegenerative diseases such as Alzheimer’s and Parkinson’s could potentially be cured if ES or iPS cells could be coaxed into differentiating in culture into appropriate neurons and if a method could be found to deliver those neurons to the appropriate regions of the brain. Similarly, ES and iPS cells can form normal-looking red blood cells and other types of blood cells in culture—but are these cells truly normal and completely functional, and can a bioengineering protocol be developed to make these cells in sufficient purity and numbers for transplantation into humans? Undoubtedly these problems, which are at the interface of tissue engineering and cellular and developmental biology, will eventually be solved—the question is, how soon?

Programmed cell death is the basis for the meticulous elimination of potentially harmful cells, such as autoreactive immune cells, which attack the body’s own cells, or neurons that have failed to properly connect. Cell-death programs have also evolved as a defense against infection, and virus-infected cells are selectively murdered in response to death signals. Viruses, in turn, devote much of their effort to evading host defenses. Failures of programmed cell death can lead to uncontrolled cancerous growth. The proteins that prevent the death of cancer cells are therefore possible targets for drugs. As we will learn in Chapter 24, many tumors contain a mixture of cells, some capable of seeding new tumors or continued uncontrolled growth and some capable only of growing in place or for a limited time. In this sense, the tumor has its own stem cells. These cells are now being identified and studied and are becoming vulnerable to medical intervention. One option is to manipulate the cell-death pathway by sending signals that will make cancer cells destroy themselves.