The Mysterious Embryonic Stem Cell

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Stem cells are mysterious. They are cells that make or replenish other cells. For example, when you donate blood, your stem cells are in charge of replenishing your blood cells. Scientists have found stem cells throughout the body, each doing an assigned job. Some replenish blood cells, some replenish skin cells, and others repair heart tissue. These cells do not usually change jobs; they become specialists at making their particular cell types.

However, embryonic stem cells (ESC), those found in the eight- to ten-day-old embryo, are not specialists. They can make all the cells in the body, but how they are able to accomplish this feat is still unknown.

Researchers have been able to coax some of these specialized stem cells into reverting back to a stem cell that acts like an embryonic stem cell. These are call "induced pluripotent stem cells." As with embryonic stem cells, scientists are still seeking the keys to how these cells can develop into specific stem cell types. Interestingly, research on embryonic stem cells and induced pluripotent stem cells seems to indicate that stem cells are pre-programmed to do their thing, suggesting that this may be a case of an intelligently designed process. (See ENV, "A Piece from the Developmental Symphony").

Two compelling scientific articles this past month provide some hints of how stem cells are programmed. One study, in Molecular Cell, shows that embryonic stem cells will readily undergo apoptosis (cell death) if DNA is mis-copied, but once the embryonic stem cell gets assigned a job (i.e. differentiates), this sensitivity to apoptosis is "turned off." In other words, the cell has a layer of protection in place at just the point when a DNA error would spread throughout the entire organism, potentially causing irrevocable damage. And, just as conveniently, this heightened sensitivity to DNA damage is turned off at just the point when the cell starts to differentiate.

The key player in this process is the Bax protein. This protein is known to signal apoptosis, and is present in its active conformation in the ESC. Through a series of signals, Bax is "turned off" whenever the cell starts to differentiate. But during the delicate DNA replication process in the early embryo, the protein is active to ensure fundamental DNA errors are not perpetuated throughout the organism. Additionally, and adding yet another layer of complexity to this system, Bax is active, but other factors, including the location of the Bax protein, are in place to ensure that the cell does not undergo apoptosis prematurely.

A second study published in PLoS Genetics demonstrates that the level of DNA compaction affects stem cell differentiation. Scientists have long known that stem cells have loosely packed DNA compared to differentiated cells, which probably aids in DNA replication at the early embryonic stages. In eukaryotic cells, chromatin is involved in many DNA processes, including packing the DNA so that it fits inside the cell. The primary proteins in chromatin are called histones. Think of the histone/DNA complex as spools of yarn. The DNA wraps tightly around the histone so that the small spool, rather than the long DNA strand, can fit inside the cell. There are several families of histones, and only some of them are involved in the processes under consideration in this study. For the sake of simplicity, we will simply refer to them as histones. Please refer to the research article for a more detailed description of which histones are involved in which processes.

It seems that there is a coordinated link between DNA compaction and pluripotency. When one of the histones involved in DNA compaction was removed, the mouse embryonic stem cells did not differentiate properly. The stem cells did not get their assignments, as they normally would. The DNA must be loosely wound during the early embryonic stages, but as the embryonic stem cells differentiate (assigned to a specific cell type), histone levels increase and the DNA becomes more tightly wound around the histone.

The key protein players in the pluripotentcy process are Nanog and Oct4Nanog and Oct4 are regulated via DNA methylation, and as this study found, the absence of certain histones, and therefore the presence of loosely wound DNA, keeps Oct4 "turned on." Usually Oct4 gets "turned off" as the cell transitions from a pluripotent stem cell to a differentiated stem cell. If Oct4 stays activated, then the ESC never undergoes differentiation.

The authors conclude:

Our results suggest a role of H1 [histone] and chromatin compaction in epigenetic regulation of the pluripotency gene Oct4, likely mediated through DNA methylation and histone modifications. To our knowledge, this represents a novel mechanistic link by which bulk chromatin compaction is directly linked to pluripotency, by participating in repression of the pluripotency genes.

This is not a simple case of cause-and-effect. Note that several factors are in place and each activates and inactivates in turn, as if programmed to do so.

In both of these studies, there are proteins that are "turned on" and "turned off" at just the right time so that the complicated ensemble of development processes can occur. These are epigenetic factors that affect the complex process of cell differentiation.

In any other context, we would consider this type of complexity, with a program that tells the components what do and when to do it, a hallmark of the most sophisticated engineering. Those kinds of instructions do not just arise in a kind of add-on or co-opted Darwinian method. The more we delve into the inner working of the cell, the more we see how complicated it is -- complicated in a way that suggests purpose and design.

In case you were wondering, by the way, the studies on embryonic stem cell apoptosis were performed with human embryonic stem cells. The stem cells came from a stem cell line at the University of Wisconsin. Human embryonic stem cell research is, of course, the subject of considerable moral controversy. Some people believe the human embryo should be accorded the same dignity as a human person, while others think that the human embryo, while it is human tissue, is not morally equivalent to a human person.

Even though this research does have compelling implications for intelligent design, we recognize that the methods by which the results were obtained, while legal in the United States, are very much open to question on ethical grounds. Furthermore, we recognize that scientific studies usually begin with animal systems before advancing to human systems, but the scientists in this study chose to investigate human systems. The scientists in the DNA and chromatin study, on the other hand, used mouse systems to derive their data.

Image credit: human embryonic stem cells, Wikicommons.

Evolution News & Views May 26, 2012 7:00 AM,