By Shirley Lee
Featured image: Induced pluripotent stem cells stained red, their nuclei are stained blue. Source.
When I was first taught the process of embryonic development in biology class back in high school, I was amazed by the complexity of the process. Each one of us was derived from a single cell (the result of the joining of an egg and a sperm), which then went through countless cell divisions. It amazes me that something so small is packed with so much biological potential!
Naturally, scientists set out to get to the bottom of this phenomenon. In the 1990s, people discovered how to extract these cells (called stem cells) from developing human embryos in order to study the process underlying stem cell development in research laboratories. It was quite a controversial topic that sparked an entire debate on whether this activity is considered ethical because the human embryo would be destroyed in the process (it also re-sparked numerous philosophical debates, about when life begins, whether human embryos are considered ‘people’, do human embryos have rights, and should the act of destroying human embryos constitute murder; Or do stem cells turn into human babies, Figure 1). Shortly after the discovery of stem cell extraction, federally funded stem cell-related research activities were restricted by the Bush administration in early 2000s, allowing only a small subset of stem cell-derived cell lines for research activities. (For a laugh, see the stem cells cartoon by Glenn McCoy).
Since federal funding on stem cell research in United States was restricted in early 2000s, an impetus existed in the scientific community on finding alternatives to continue studying stem cells. As a result, groundbreaking research published by Shinya Yamanaka and colleagues in 2007 showed us how to take any cell in the body and give these cells the ability to become any other cell. These newly lab-developed stem cells, termed induced pluripotent stem cells, or iPSCs, have revolutionized the stem cell field and helped numerous scientists continue their work. This resulted in bypassing the need to extract human stem cells from developing embryos and quiets some protest to stem cell research. Yamanaka was awarded a Nobel Prize in 2012 for this groundbreaking contribution.
As mentioned before, iPSCs can be made from any cell in the body, including cells that are already fully developed, which is a different origination from the human embryonic stem cells. This induced pluripotency phenomenon is quite a surprise,given everything we knew about the stem cells up until the time of Yamanaka’s discovery, and the process of cellular development was thought to be irreversible. It was thought that as one stem cell begins the process of becoming a hair cell,for instance, its ability to become another type of cell (like a skin cell) gets weaker and weaker. When the stem cell finally becomes a fully developed hair cell, it can only be a hair cell for the rest of its lifetime (until we take it into the lab and realize its cell type identity is not set in stone). similar to those crazy aspirations we had we were little; a young child has all the potential to become an astronaut, a doctor, a painter, or a firefighter when s/he grows up. But as the child ages and gets more educated, s/he becomes more and more committed to a certain career path, and switching paths is harder to do (though not impossible!). The ability of a cell to turn into other types of cell, or cellular differentiation, is very similar. Cells are ranked by five different levels of ‘versatility’: totipotent (the most versatile type of cell, that can grow into a new mammal and its placenta), pluripotent (it can only grow a new mammal), multipotent, oligopotent, and unipotent (this is the least versatile type of cell, like the previously mentioned hair cell). As the word ‘pluripotent’ in the name indicates, iPSCs rank rather high on the versatility ladder, and this underlying process of iPSCs creation is closely tied to epigenetic regulation.
Epigenetic regulation is the process that controls gene expressions without changing the physical DNA sequence in the genome. Each type of cell in our body has a unique epigenetic profile that corresponds to its cell type identity. Interestingly, in the presence of the Yamanaka factors (four critical proteins commonly found in an embryonic stem cell to maintain its properties), a series of molecular events are triggered to reset the cell’s epigenetic profile back to a profile similar to that of an embryonic stem cell, with most of its natural properties present. Critical genes related to maintenance of the stem cell’s properties are all turned on, and other developmental genes now have both ‘active’ and ‘silence’ marks on them, and it is the cell’s way of telling its transcription machinery ‘please standby for further instructions on these genes’. This process is in theory applicable to all cells in the body, but reversion is easier and more efficient for cells that are more stem cell-like (they are higher on the versatility ladder, with an epigenetic profile closer to that of a embryonic stem cell) than the cells that are less stem cell-like.
Fast forward to 2016. The stem cell field is presently one of most active areas of scientific research. However, more work remains to be done to fully understand the underlying molecular events of induced pluripotency before scientists can confidently state that iPSCs are equivalent to human embryonic stem cells. But scientists have taken these iPSCs one step further – major effort is already in motion to benefit human health. A major usage of iPSCs is using them to basically help regrow a patient’s diseased organ as new treatment. A couple of on-going clinical trials concentrate their efforts of regenerating brand new organ tissues using iPSCs from patients with type I diabetes, retinal degeneration, or coronary artery disease (just to name a few) as a way to prevent complications that often arise after organ transplants. Although we don’t yet completely understand everything about how a cell can be reprogrammed, the future is bright with stem cell applications.
About the author
Shirley is currently a PhD student in Molecular and Cellular Pathology at the University of Michigan. Under the supervision of Dr. Yali Dou, she is searching and developing drug candidates for Mixed Lineage Leukemia (MLL), and simultaneously, trying to understand why things are so complicated in leukemia. Before joining the Dou Lab, Shirley attended the University of Maryland, College Park and got her bachelors in Biochemistry. When not in lab, Shirley enjoys running or training for the next road race, reading, listening to music, and just hanging out with her two rescued cats Samantha and Marco.
You can read all posts by Shirley here.