Specialisation of cells underpins the effective functioning of the human body. Red blood cells need to be specialised for their role of transporting oxygen, whilst muscle cells are well adapted for contraction and movement. Specialisation is no doubt important, but what if there was a way we could reprogram specialised cells back to their original forms? – back to immature ‘embryonic like’ stem cells that are capable of developing into any tissue type within the body. This would allow us to understand more about the cell developmental process, as well as create a potential new avenue for therapeutic designs.
Well in 1962 John B. Gurdon performed experiments in frogs which showed that specialisation of cells is reversible. Many years later in 2006 Shinya Yamanaka discovered how this process takes place. Yamanaka was successfully able to reprogram mature cells in mice back into immature stem cells and coined the term ‘induced pluripotent stem cells’ (iPS cells) to describe the new cells he had created. This is now a globally recognised term within biology. Gurdon and Yamanaka’s research was a ground breaking discovery in the scientific world and led to them jointly receiving the Nobel prize in 2012. Their research has given rise to new fields of study as we can now reprogram various human cells to help treat diseases and create new therapeutic compounds1
What did Yamanaka’s research entail?
Yamanaka used knowledge of embryonic stem (ES) cells for the basis of his experiments. Embryonic stem cells are immature cells derived from the developing embryo, and their defining feature is that they are pluripotent, which means they can develop into a variety of different cell types and don’t have a set fate. Yamanaka selected 24 genes responsible for this pluripotent characteristic in embryonic stem cells and inserted them into specialised mouse cells to see if these genes would cause the specialised cells to revert to a more premature pluripotent state. To assess whether or not this transition took place, he added neomycin resistance genes to the cells which would be activated if the cell became pluripotent. Neomycin is an antibiotic which would normally kill cells, however if pluripotent cells express a gene for resistance against the antibiotic, those pluripotent cells would survive against high concentrations of the antibiotic and be detected. Any cells that survived the antibiotic treatment would be evidence that the specialised mouse cells had returned to a more developmental, pluripotent state2.
Yamanaka’s research was a success and some of the cells survived when lethal concentrations of antibiotic were added. Following these results he repeated the experiment with different combinations of the 24 genes, and found that the smallest combintation of only 4 genes were required to observe pluripotency in cells and create induced pluripotent stem cells (iPS cells)2. The figure below3 is a simplification of the experiment and shows the potential fates of iPS cells.
How are iPS cells used in medicine today?
Since this research took place in 2006, Yamanaka’s technique has been refined and there are now a number of different ways to generate these ’embryonic like’ iPS cells, including the use of proteins and vectors. iPS cells have been used for a variety of clinical purposes such as assessing toxicity of drugs for treatment purposes, as well as in organ and tissue transplants. Before drugs and other compounds are mass produced, they need to be tested for toxicity levels to see what sort of effects they can have. iPS cells act as a great model for testing these compounds which are encountered by humans as the iPS cells can be cultured in the lab. Additionally, iPS cells also aid in organ transplants as there is less of a likelihood of the cells being rejected by the body because the cells can be taken from the specific patient in question. This method of transplant also reduces some of the ethical issues surrounding the use of embryonics stem cells for transplants 4. More recently iPS cells have been used in the study Hepatitis B infections5 and polycystic kidney disease6.
What are the challenges faced when using iPS cells?
As with many therapeutic techniques, there are certain challenges that come with the use of iPS cells. iPS cells have shown to have more variability than normal embryonic stem cells and can obtain new features during the the reprogramming process7. Equally, the 4 genes introduced into the cells during the process to generate pluripotency can be over expressed, generating tumors and other defects8. Whilst using iPS cells is perhaps a more ethical approach in comparison to embryonic stem cells, the use of iPS cells may also divide opinion and impose its own ethical issues.
Gurdon and Yamanaka’s research which led to the creation of iPS cells was a defining moment within cellular biology, and created new avenues for research and disease control. Advances have been made in areas of evolution, cancer biology and cellular and molecular biology as a result of these findings7. Whilst it is clear that there is future potential for the use of iPS cells in research, the field is still being explored and will need to be studied further in order to know its full potential.
- “The Nobel prize in physiology or medicine 2012” https://www.nobelprize.org/prizes/medicine/2012/summary/
- Takashi. K, Yamanaka. S “Induction of Pluripotent Stem Cells from Mouse Embryonic and Adult Fibroblast Cultures by Defined Factors”, Cell, 2006
- Singh V.K, Kalsan M, Kumar N, Saini A, and Chandra R “Induced pluripotent stem cells: applications in regenerative medicine, disease modeling, and drug discovery” frontiers in cell and developmental biology, 2015
- Chen S-W, Himeno M, Koui Y, Sugiyama M, Nishitsuji H, Mizokami M, Shimotohno K, Miyajima A & Kido T. “Modulation of hepatitis B virus infection by epidermal growth factor secreted from liver sinusoidal endothelial cells” Nature 2020
- “Reproducing the pathophysiology of polycystic kidney disease from human iPS cells” https://www.eurekalert.org/pub_releases/2020-08/ku-rtp082120.php
- Ohnuki M and Takahashi K. “Present and future challenges of induced pluripotent stem cells”, Philosophical transactions B, 2015
- Medvedev S.P, Shevchenko A. I , Zakian S.M. “Induced Pluripotent Stem Cells: Problems and Advantages when Applying them in Regenerative Medicine” Acta Naturae, 2010