The fantastic four

Before I launch lead long into the field of epigenetics, I would just like to explain what a stem cell is. The pluripotent stem cells, generally thought of as the gold standard of stem cells as they can become any cell type other than placental tissue, we can harvest from a blastocyst early in development. The inner cell mass, that would become the embryo later on, is removed from the trophoblast (the developing placenta) and specially cultured to form pluripotent Embryonic stem cells (ES cells). They may be difficult to produce, but these ES cells can divide an infinite number of times, and if you have the right culture conditions, you can make almost any cell type. For example ES cells can differentiate into autorhythmic cardiomyocytes that beat, if you can imitate the conditions of the heart in a culture.

Now onto the main course, the Japanese doctor-turned-geneticist Shinya Yamanaka. Yamanaka spent a huge amount of time and resources trying to identify the genes expressed in ES cells, which allow them divide infinitely and differentiate into almost any other cell, but which are silenced after the cell has differentiated. He started his investigation with a list of 24 genes, knowns as 'pluripotency genes', which were thought to be vital in ES cells.  Yamanaka tested combinations of these genes, to see if they would cause a differentiated cell to move back up Waddington's epigenetic landscape(picture on right) and become pluripotent again, a huge risk to take - putting his career on the line for scientific progress; that's what I call dedication. He tested the combinations of his 24 genes in mouse embryonic fibroblasts (connective tissue cells) (MEFs). These cells were taken from embryos, as the name implies, and Yamanaka was hopeful that they would retain some of their capacity to convert into early cell types in the right culture. However, the mice cells used were special, they contained an extra gene known as the neomycin resistance gene, giving the cells resistance to the normally deadly compound neomycin. The gene was inserted into the genome in a way that meant cells would only express it, and survive neomycin if they became pluripotent. When all 24 genes were inserted in vectors simultaneously, only a tiny fraction of cells became pluripotent and survived the neomycin. However, the winning combination, of only 4 genes in fact, was;Oct4, Sox2, Klf4 and c-Myc. These 4 genes allowed cells to survive neomycin poisoning, and even change their appearance to look like ES cells. Yamanaka christened his discovery 'induced pluripotent stem cells', and the 4 genes are forever known as the 'Yamanaka factors'. What I find most incredible about this breakthrough is, that despite the fact our cells contain around 20,000 genes, only 4 are required to produce a pluripotent cell. It just goes to show the immense power even individual genes wield within the human body...