When visiting the meat counter of a supermarket, one does not need a microscope to see that liver and steak are different. They are different because their constituent cells are different. Microscopic observation confirms this notion. Liver cells differ from muscle cells in morphology (structure) and this difference is a reflection of physiological activities and biochemical functions that are ultimately under the control of genes. The differences that can be seen grossly (as at the meat counter), observed in the microscope, and detected by biochemical and molecular procedures together comprise what is known as differentiation.
Differentiation results from selective gene action of a genome (the entire genetic complement of an organism) held in common by all cells has been a tenet of modern genetic biology. Certainly the recent cloning of Dolly and other mammals supports this concept. It is the business of a cell to produce all of the proteins and enzymes held in common by most cells. The commonly produced gene products are sometimes referred to as housekeeping proteins. However, the adult fly, frog or human are comprised of a great diversity of differentiated cells. The differentiated cells produce, in addition to the housekeeping gene products, tissue-specific proteins. A unique portion of the genome of differentiated cells is activated and this accounts for differentiation. While all other cells have these gene sequences, they are silent except in the specific cell type under consideration. Thus, liver differs from muscle not because of its genome, nor because of the activity of housekeeping genes, but by the activation of tissue-specific genes which convey cell specificity. Gene regulation that permits differentiation is the result of promoters and enhancers (which occur in DNA on either side of specific genes) and regulatory proteins which bind to the promoters and enhancers and which in turn enhance or inhibit gene expression.
Differentiation is associated with embryology. The undifferentiated cells of a zygote, morula, and blastula give rise to progressively more differentiated cells until the adult forms which is a mosaic of many highly differentiated cells. Ordinarily, differentiated cells have lost the competence to give rise any other kind of cell. Therefore, muscle never gives rise to liver and vise versa. Moreover, contained within the mosaic of terminally differentiated cells are a number of stem cells. A stem cell is a less than fully differentiated cell that has retained the competence to give rise to another stem cell and a cell that will become fully differentiated. Consider the skin--it would rapidly be lost because of abrasion and the wear and tear of use were it not for replacement by cells from the basal layer of epidermis. Differentiation of the skin stem cell progeny gives rise to post-mitotic keratinized protective cells. Blood is a tissue type that must be continually replaced. It is not surprising, therefore, to note that new blood cells develop from stem cells, which like skin stem cells, at division give rise to both more stem cells and cells which will differentiate as blood.
A final note about differentiation. Cancer is believed by many to not be a malignancy of fully differentiated adult cells, most of which have lost their potential for cell division. Rather, cancer is viewed as a disease of stem cells. Stem cells appear less than fully differentiated. Cancer cells appear less than fully differentiated. Stem cells are characterized by their mitotic (cell division) potential. Cancer cells are well known for their mitotic potential. Many fully differentiated cells are post-mitotic, i.e., they no longer retain the competence to divide. These ideas have given rise to the notion that, under appropriate circumstances, perhaps cancer cells could be induced to differentiate. A non-proliferating terminally differentiated cell would result which, by definition, is a cure. Differentiation is occurring in normal cells continuously. It is neither painful nor toxic. Perhaps someday, some cancer will be treated by differentiation therapy and if so, the therapy may be neither painful nor toxic. All-trans retinoic acid, a form of vitamin A, has induced remission of acute promyelocytic leukemia. While this is not a cure, it provides hope that differentiation therapy may have a place in the treatment of some cancer.
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