Imagine you have in front of you a complex spaceship made of Legos. It’s pretty cool. Still, those Lego blocks could have been assembled into a variety of other things—maybe a skyscraper or a sports car. The blocks have amazing potential and flexibility.

Similarly, every higher organism’s DNA has in place all the instructions necessary to make the wide variety of cell types the organism needs. Human DNA, for example, has the blueprint for bone cells, blood cells, nerve cells, and many others.

Normally, a certain type of cell divides to give rise only to cells close to its own type—skin cells divide to make more skin cells, and so on. Although the potential for flexibility exists, somehow it has been lost. If scientists could encourage cells to undo the specificity they display (nudge skin cells to divide to produce bone or nerve cells as well as skin cells, for example), that understanding might be used in medical treatments to generate tissues or organs that have been damaged through accident or disease such as cancer.

One means by which scientists think cells may be able to make large-scale shifts in their DNA expression and, therefore, their behavior, is to change the methylation pattern of the DNA. Methlyations are small molecular changes added to DNA bases that, when present in large numbers, are known to have the effect of silencing genes on a large scale.

The enzymatic mechanism by which methylations are added (or, how a particular spaceship is put together) has been understood for a long time. But the mechanism to reprogram a DNA structure that fixes cells on a specific pathway of behavior (or, how to remove some Lego blocks from the spaceship to then turn it into a skyscraper) was not understood.


Recently, Huntsman Cancer Institute (HCI) investigators David Jones, PhD, Senior Director of Early Translational Research and professor of oncological sciences, and Bradley Cairns, PhD, professor of oncological sciences, identified a two-step molecular path by which methyl groups can be removed from DNA in the zebrafish, a simple vertebrate animal that serves as a model for higher vertebrate systems such as humans. Their work provided evidence that demethylation is a coordinated system in which a particular biochemical change is made to a methylated DNA base that results in a mismatch in the DNA double helix. Associated, separate proteins then act to excise and repair the mismatch in the DNA.

Now that a mechanism is clear, researchers can study the effects of demethylation on cells and evaluate the potential of cellular reprogramming. It may be that as a result of demethylation, the Lego blocks of the cell are stored to their unbuilt state. If so, then the demethylation process might enable new shapes to emerge—even the possibility that cancer cells characterized by too many methylations might be converted into normal cells. This is just one of many possibilities that can now be pursued in light of Jones’ and Cairns’ work, and another example of HCI investigators working to understand cancer from its very beginnings.