Pluripotent Stem Cells and the Nobel Prize for Medicine

Reading time: 4 – 6 minutes

The 2012 Nobel Prize in Physiology or Medicine was announced earlier this week. The prize was awarded to two scientists for their work on reprogramming mature cells to become pluripotent.

The prize of 10-million-Swedish-krona (US$1.5-million) was divided, one half jointly to Sir John B. Gurdon, age 79, at the Gurdon Institute, Cambridge, United Kingdom, and Shinya Yamanaka, age 50, at Kyoto University, Kyoto, Japan and the Gladstone Institutes, San Francisco, California, USA, for the discovery that mature, specialized cells can be reprogrammed to become immature cells capable of developing into all tissues of the body.

Reprogramming a differentiated cell to become pluripotent

We all develop from fertilized egg cells. Following conception, the embryo consists of immature, dedifferentiated cells, each of which is capable of developing into all the different cell types that form the adult organism. These immature, dedifferentiated cells are called pluripotent stem cells.

As the embryo continues to develop, the immature pluripotent cells give rise to specialized cell types: nerve cells, muscle cells, liver cells, etc. The widespread view during the first half of the 20th century was that the  journey from immature to specialized cell — called cellular differentiation — was considered to be a one-way street. It was thought that mature, differentiated cells couldn’t return to an immature, pluripotent stage.

John B. Gurdon challenged the dogma that the specialized cell is unable to become pluripotent again. Gurdon hypothesized that the genome of a mature cell might still contain all the information needed to direct its development into all the different cell types of an organism. In 1962, he tested this hypothesis by replacing the cell nucleus of a frog’s egg cell with a nucleus from a mature, specialized cell derived from the intestine of a tadpole [1]. The egg developed into a fully functional, cloned tadpole. Subsequent repeats of the experiment yielded adult frogs, showing that the mature cell nucleus still had the information necessary to drive development and differentiate into a fully functional organism.

While a landmark discovery, Gurdon’s research involved the replacement of cell nuclei. More than forty years later, Shinya Yamanaka identified the specific genes responsible for reprogramming mature cells to become pluripotent stem cells. Just four genes — POU class 5 homeobox 1 (POU5F1), SRY (sex determining region Y)-box 2 (SOX2), v-myc myelocytomatosis viral oncogene homolog (MYC), and Kruppel-like factor 4 (KLF4) — could induce a differentiated cell to become pluripotent; such “pluripotent stem cells (iPS cells)” could then be reprogrammed into different mature cell types. The recipe was published in 2006 and was immediately considered a major breakthrough [2].

Today, companies like Cellular Dynamics International, Inc. develop stem cell technologies based on induced pluripotent stem (iPS) cells for drug development and personalized medicine applications. Stem cells, including iPS cells, can potentially be used to replace diseased or lost cells in degenerative disorders, such as Parkinson’s disease and type 1 diabetes. Cell replacement therapy with iPS cells can also allow cell grafting that would be less prone to immune rejection since the cells are from the same person. Lastly, using iPS cells derived from patients with genetic and other disorders allows scientists to gain novel insights into disease processes.

References

1. Gurdon JB. The developmental capacity of nuclei taken from intestinal epithelium cells of feeding tadpoles. J Embryol Exp Morphol. 1962 Dec;10:622-40.
   View abstract
2. Takahashi and Yamanaka. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006 Aug 25;126(4):663-76. Epub 2006 Aug 10.
   View abstract