Stem cells from a biological perspective: what they are, where they are found, and what can be done with them.

• Author: Niemi, William D.

Cells are the smallest living units of living systems. They can respire, respond, and reproduce. A single human cell, however, or even a conglomerate of human cells, does not a human being make. In fact, the human body is made up of trillions of cells that are organized into specialized tissues and organs, and many of these cells die each day and need to be replaced by new ones. Unspecialized and undifferentiated cells that are dormant are called upon to renew or repair the body; these are the so-called stem cells.

A given human being is never the same conglomerate of cells from day to day, but somehow remains the same person. It is the nervous system that provides the property (or, perhaps more correctly, the illusion) of sameness, i.e., the continuity of self. It is the organization and the activity of neuronal cells that allows for the emergence of the mind--for awareness, memory, and self-identity. It is the nervous tissue, therefore, that is most identified with "humanness." For this reason, the taking of stem cells from embryos in which no nervous tissue has yet appeared has received more acceptance than the taking of stem cells from more developed embryos or fetuses. (1)

Recent evidence indicates that even in the nervous system some cell turnover can occur, (2) but this seems limited to a few specific areas and has not been observed in a non-pathological or non-treated human patient. In other words, evidence so far has only been gathered from autopsies of chemotherapeutically-treated patients. The assumption that brain cell turnover occurs normally rests mainly on animal studies and, even there, turnover is very limited. (3)

Stem cells are undifferentiated cells and have the potential to become many cell types and to form various tissues by mitosis (multiplication) and differentiation (specialization). The mother of all stem cells is the zygote, a fertilized egg cell that can give rise to every part of the human body and, therefore, is considered totipotent--capable of forming both embryonic and extraembryonic tissue (placenta and yolk sac). Totipotency is also characteristic of cells from the next six cell divisions of the zygote. During the first week (around day three) the zygote has divided to form a solid ball of cells called the morula (thirty-two cells, each of which is a totipotent stem cell). (4) One could theoretically harvest the cells of the morula prior to blastocyst formation; each of these thirty-two cells is capable of producing both placental and embryonic tissue and therefore has totipotentiality while the inner cell mass of a later embryo has pluripotentiality. By the end of the first week of embryonic development, a blastocyst (a ball of cells with a cavity containing an oval disc of cells--the embryonic disc) is present containing an inner mass of 128 cells. (5) In natural development this point in time would also coincide with implantation in the uterine wall, although not all blastocysts implant--some pass out the uterus. It should be noted that if a splitting of the inner cell mass were to occur at this time, identical twins (or even triplets) could develop in the implanted embryo. (6)

Human embryonic stem cells (HESCs) are usually isolated manually from the inner cell mass of an embryo grown in vitro by a skilled technician using a micromanipulator-controlled micropipette and microscope. These inner mass cells, if separated and cultured in vitro, can give rise to all tissue types (pluripotency), but not a placenta. Therefore, they have no potential to develop into a human being. In the second week, the inner cell mass divides into three layers and these cells are considered to be multipotent, capable of becoming a number of different tissue types, but not as many types as a pluripotent cell can. As development proceeds (i.e., additional cell divisions), these cells become more differentiated and their multipotentiality and their self-renewal ability decreases, making them less desirable for treatment or transplant. In the third week of development, we see a primitive streak and then a neural groove indicating that progenitor cells of the nervous system have taken up their positions. It is both scientifically and ethically preferable to harvest stem cells before this time.

During development various stem cells take a "fork in the road" of development, and proceed on a path of differentiation toward specialization, thereby becoming committed to being a specific cell type. They do not "backtrack" under normal conditions, although backtracking to a limited extent has been recently achieved in vitro. (7) Some stem cells halt their differentiation midstream and reside in the adult body as pools of "committed" stem cells tucked away here and there--difficult to detect and isolate (sometimes referred to as progenitor cells because they will give rise to cells of a particular lineage). There is some question about the extent of commitment these adult stem cells possess. Are some of them as "naive" as embryonic stem cells? Unique markers expressed at the stem cell surface are being discovered as this paper is written, and these will make stem cell isolation and characterization easier. (8)

Normal stem cells seem to obey the "Hayflick limit," (9) i.e., they will divide approximately fifty times and then undergo senescence. Maintaining stem cell inventories required starting new cultures from new embryos. A breakthrough in culturing embryonic stem cells occurred in 1998 when James Thomson of the University of Wisconsin discovered a line of so-called...