A bitter controversy raged in biology from the late 1990s to 2007 over whether or not research using human embryonic stem cells (ESC) is ethically permissible. Opponents of this research pointed out that to obtain embryonic stem cells human embryos must be killed, whereas proponents pointed to the great potential of ESC in human medicine.
Then, in 2007, Shinya Yamanaka described how to transform ordinary human adult cells into ESC-like stem cells called induced pluripotent stem cells (iPSC). Yamanaka won the 2012 Nobel Prize in Physiology or Medicine for this work. iPSC seemed to have the same medical potential as ESC but without the ethical problem because no killing of embryos is necessary to generate iPSC. Many scientists using ESC quietly switched over to iPSC, and the controversy died down. However, it was not clear if the artificially generated iPSC were as good as the natural ESC, and many scientists advocated continuing ESC research in tandem with iPSC. Now, a paper published online in Nature Biotechnology by Konrad Hochedlinger and others compares the capacities of ESC and iPSC and finds that the two are functionally equivalent.
The cell is the fundamental unit of biological organisation and the human body is composed of trillions of cells. Most body cells are the differentiated specialised cells that make up the body’s organs and tissues: liver, kidney, skin, blood and so on. Stem cells are undifferentiated cells that have the capacity to change into a variety of specialised tissue cells.
There are three types of stem cell. Two types reside in the body and the third is made artificially by manipulating ordinary body cells. Firstly, organs and tissues contain small numbers of stem cells called adult stem cells. Secondly, at the start of human life the embryo contains ESC, and thirdly, it is possible to genetically transform specialised adult cells into iPSC that behave like ESC.
The range of cell types into which stem cells can change is called potency. Thus, multipotent adult stem cells can only differentiate into the specialised cells of the organ in which they are found, and perhaps into a small range of related cell types. ESC and iPSC are pluripotent: able to differentiate into each of the more than 200 types of specialised cells in the body.
Stem cells have great potential in regenerative human medicine because in principle they could be used to grow new organs or tissues to replace failing organs or tissues. The greater the stem cell potency, the greater the medical potential – ESC and iPSC have greater potential than adult stem cells. But is iPSC as good as ESC?
Studies show that different genes are switched on in iPSC compared with ESC. Does the reprogramming of adult cells into iPSC change the cells’ ability to regulate their genes, making iPSC behave differently to ESC? ESC and iPSC are inherently genetically different because they come from different sources, and it is difficult to tell whether genetic variations noted between the two cell types are due to source difference or to the reprogramming process itself.
To investigate this question, Hochedlinger and his team took two male ESC cell lines, matured them into skin cells and genetically transformed these skin cells into iPSC. These iPSCs genetically matched their ESC parents. Measurement of gene activity showed that the iPSCs were more similar to their ESC parents than to each other, indicating that cell source explains most of the disparities researchers note between iPSC and ESC.
The ultimate test of a stem cell is its ability to change into different cell types. The researchers found that iPSC and ESC were equally good at this. Hochedlinger commented: “The two cell types appear functionally indistinguishable based on the assays we used.” This latest research is a major milestone on the road to demonstrating that iPSC can do everything for medicine that ESC can.
Shinya Yamanaka’s primary motivation to develop iPSC was ethical. He resolved to develop a method to make stem cells equivalent to ESC by a route that would not entail destroying human embryos. It looks like he has fully realised his dream.
William Reville is an emeritus professor of biochemistry at UCC.understandingscience.ucc.ie