Nobel-Winning Discovery of Cellular Reprogramming Paves the Way for Personalized Medicine

While Nobel Prize 2024 announcements are approaching, let’s go back to 2012. The Nobel Prize in Physiology or Medicine 2012 was awarded to Dr John B Gurdon and Dr Shinya Yamanaka for the discovery of reprograming mature cells to pluripotent cell state[1]. Previously, differentiation thought to be unidirectional as Waddington described cell differentiation using a metaphor that differentiation was rolling down from a mountain[2]. Dedifferentiation would be difficult as like moving marbles back to the mountain top.

Gurdon showed that a small number of swimming Xenopus laevis tadpoles were generated when enuclated eggs were transplanted with nuclei from tadpole intestinal epithelium[3]. Gurdon’s discovery showed that the cell nucleus from a somatic differentiated cell has the capacity of somatic cell development with a full range of cell types. This technique was used in different studies, perhaps the most well-known is the sheep Dolly [4].

New questions arose about possibility of induction of an intact differentiated cell to dedifferentiate. Even though, the answer was “impossible” for many scientist, Yamanaka decided to work on induction of pluripotency in somatic cells. Yamanaka knew that a large set of transcription factors were expressed in embryonic stem cells to maintain the pluripotency. Firstly, 24 genes were selected and then the number of genes were reduced to four transcription factors (Myc, Sox2, Klf4, and Oct3/4) [5]. Yamanaka called these cells “induced pluripotent stem cells (iPSCs)”. After this discovery in mouse fibroblast cells, scientists started to work on human cells. In 2007, Yamanaka’s and James Thomson’s research groups were the first to produce human iPSCs by using different transcription factors.

The technology has been improved and different groups have shown that expression of specific transcription factors can directly convert somatic cells to different differentiated cells. Even though this direct reprogramming technology has important advantages, it comes with concerns over the safe usage of the cells in clinic (due to tumorigenicity). These concerns caused a shift in the field towards chemical based reprogramming strategies. Recently, 1-year results from one patient of a first-in-human phase I clinical trial has been reported. In the clinical trial, chemically induced pluripotent stem-cell-derived islets (CiPSC islets) were used for autologous transplantation in type-1 diabetes [8]. The report shows promising results in achieving the potential of personalized cell therapy using autologous CiPSC transplantation to treat disease.

References:
1. The Nobel Prize in Physiology or Medicine 2012. NobelPrize.org. Nobel Prize Outreach AB 2024. Sun. 6 Oct 2024. https://www.nobelprize.org/prizes/medicine/2012/summary/
2. Waddington CH (1957) The Strategy of the Genes; a Discussion of Some Aspects of Theoretical Biology. Allen & Unwin
3. Gurdon JB (1962). Developmental Capacity of Nuclei Taken from Intestinal Epithelium Cells of Feeding Tadpoles. J Embryol Exp Morph 10: 622-­‐640.
4. Wilmut I, Schnieke AE, McWhir J, Kind AJ, Campbell KHS (1997). Viable offspring derived from fetal and adult mammalian cells. Nature 385: 810-­‐813.
5. Takahashi K, Yamanaka S (2006). Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126: 663-­‐676.
6. Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K et al (2007). Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131: 861-­‐872.
7. Yu J, Vodyanik MA, Smuga-­‐Otto K, Antosiewicz-­‐Bourget J, Frane JL, Tian S et al (2007). Induced pluripotent stem cell lines derived from human somatic cells. Science 318: 1917-­‐1920.
8. Wang, S., Du, Y., Zhang, B., Meng, G., Liu, Z., Liew, S. Y., Liang, R., Zhang, Z., Cai, X., Wu, S., Gao, W., Zhuang, D., Zou, J., Huang, H., Wang, M., Wang, X., Wang, X., Liang, T., Liu, T., Gu, J., … Shen, Z. (2024). Transplantation of chemically induced pluripotent stem-cell-derived islets under abdominal anterior rectus sheath in a type 1 diabetes patient. Cell, S0092-8674(24)01022-5. Advance online publication. https://doi.org/10.1016/j.cell.2024.09.004