Question: How do some cells become brain cells and others become skin cells, when the DNA in all cells are exactly the same?

Nina Rzechorzek answered on 2 Jun 2019: last edited 2 Jun 2019 2:52 am

This is a brilliant question, and one which puzzled me when I started working with cells. All of the cells in our bodies are derived from embryonic stem cells; these cells are very special because firstly they are ‘pluripotent’ which means that can make any cell type, and secondly, they have an infinite capacity to ‘self-renew’ (make more of themselves). During development, in response to their surroundings and signals from other cells, each cell has to make ‘choices’ about which kind of cell they will become. In order for this to happen, some of the genes encoded in their DNA are expressed more (‘upregulated, activated or switched on’) relative to others (which are ‘downregulated, deactivated or switched off’). This differential gene expression makes a cell more or less likely to develop (or ‘differentiate’) into a particular cell type e.g. if the liver cell genes are switched on, it will most likely become a liver cell. In nature, we classically consider these ‘cell fate decisions’ to be irreversible – i.e. once a brain cell becomes a brain cell, it can’t go backwards and decide to become a skin cell etc. You are right however, that even once the choice has been made, almost all cells in the body will still contain the same DNA, and will be using the same bits of it to make the same basic essential proteins for cellular life. I say ‘almost all’ because a few cell types e.g. red blood cells lose their nucleus (and therefore their DNA) as they mature. The key point is that different cell types will also be making more of the proteins that are most important for the functioning of that particular cell type, using specific parts of the DNA that night be pretty redundant in other cell types. Now here’s the cool bit; scientists have discovered a way of turning mature differentiated cells back into pluripotent stem cells which can then be used in the lab to make any cell type in the body (including brain cells, which are otherwise very difficult to access and study!). This induced pluripotent stem cell or ‘iPS’ technology has been revolutionary, particularly for studying rare diseases caused by mutations in a single gene. For example, it is now possible to take a small skin sample from a patient carrying a mutation that causes a particular brain disorder, ‘reprogram’ these skin cells back into stem cells in the lab, and use them to grow brain cells to study how the mutation affects e.g. brain cell function. Because the patient’s DNA mutation will be present in all nucleated cells produced from those stem cells, the brain cells grown in the lab will also carry the mutation of interest. From what we discussed earlier, iPS technology basically works by telling mature cells to ‘turn on’ the gene expression program that specifies the stem cell identity, effectively turning back the clock of that cell to when it first existed. We can these use various developmental cues or signals to tell these stem cells to become whatever cell type we want. So that’s how a skin cell can be turned into a brain cell (in the lab at least!). Such is the importance of iPS technology today, that the work leading to its discovery resulted in Nobel Prizes for John Gurdon and Shinya Yamanaka. Groundbreaking stuff and incredibly useful!