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A Piece from the Developmental Symphony

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Embryonic development unfolds as if it were a symphony and the members of the orchestra were the various genes that are turned on and off in the course of development. Every player must perform his part at the right moment and in the right way, otherwise the delicate balance of turning on and off signals will be disrupted, with catastrophic results. Scientists have been uncovering layer upon layer of complexity that seems to point to a symphony of processes that could only have been orchestrated by design.

One of the many mysteries in embryonic development is the process that converts stem cells into other cells. During the early stages of development, the embryo is comprised of highly versatile stem cells. These cells have been of considerable interest to researchers. Because of their ability to become any cell type in the body, they are described as pluripotent.

These cells are distinguished from adult stem cells because of their level of versatility (or differentiation). Adult stem cells, such as the ones that resupply red and white blood cells or those that resupply skin cells, are only capable of becoming one or two types of cells when they are performing their normal functions within the body.

Embryonic stem cells (ESC), however, produce all of the cell types in the body. Scientists have uncovered some of the factors that can cause adult stem cells to revert to a pluripotent stage. This has been done, for example, with induced pluripotent skin stem cells. The ethics of human embryonic stem cell research is beyond the scope of this article, but it has been a hot-button issue in the media and in politics.

Researchers at the Whitehead Institute and at MIT have published a paper identifying the histone demethylase lysine-specific demethylase 1 (LSD1) as an important factor in turning off stem cell pluripotency and preparing the cell to receive instructions for its new identity as a particular cell type (e.g. nerve cell, blood cell, etc.). From the article in Nature:

We propose that the LSD1-NuRD complex decommissions enhancers of the pluripotency program during differentiation, which is essential for the complete shutdown of the ESC gene expression program and the transition to new cell states.

The authors looked at mouse embryonic stem cell development, and the LSD1-NuRD complex, in particular. Removal or inhibition of the LSD1 factor results in cell death during differentiation, but it was unclear what exactly it did that was so critical for the cell.

LSD1 is not needed in maintaining an ESC, but ESC without LSD1 died during differentiation. Additional studies showed that cells where LSD1 was silenced failed to fully transition from an embryonic stem cell to a particular cell type, indicating that LSD1 might be a key player in that transition from pluripotent stem cells to a specific cell. While the particular genes that transition the stem cell to the specific cell were activated, the genes that needed to be deactivated did not do so. The genes that tell the cell to be pluripotent were not completely shut down.

This is like starting the second movement in the symphony while your string section is still on the first movement. Rather than a smooth transition where some instruments stop and others begin, it is a noisy mess. The process breaks down and the cell dies.

Further studies showed that LSD1 is associated with the NuRD proteins, which are necessary for normal cell differentiation. While NuRD is not needed for ESC function, ESC that lacks NuRD seemed to show incomplete conversion to other cell types. Whyte et al. showed that LSD1 and NuRD interact as a complex that shuts down one cell “program” so that a different “program” may be turned on.

The authors then propose a rather intricate model for how exactly the LSD1-NuRD complex does its job of turning off the right genes at the right time. This complex interacts with a couple of key proteins used in development, and without the presence of the LSD1-NuRD complex, a link in the chain of events that lead to cell conversion is broken. LSD1’s demethylation functionality needs to be activated at the appropriate time through regulatory factors in order to shut down the pluripotency programming.

Embryonic development is an astounding process that seems to happen “automatically.” The program is in place for the embryo to develop into an organism. While evolutionary biology can account for the many small changes that occur to fully grown organisms as a response to environmental pressures, it cannot account for the origin of a process that has every indication of having the end result in mind.

The timing of each step is too precise and the complexity is too intricate to assume that these processes are the mere accumulation by happenstance of changes to regulatory genes. Each gene plays its role at a certain time, and like a symphony, each is activated and silenced in turn such that the final result is a grand performance of orchestrated effort that could only have occurred through design.

Photo credit: Seattle Symphony Chorale and Orchestra, Peter Bulthuis.