Stem cells are no strangers to media attention. In the midst of all the hype and debate, it can be difficult to determine the scientific facts. Recently, several exciting technological advances have been reported in the stem cell field, and we will explore one of them in the following article. Scientists have discovered a surprisingly simple way to re-program ordinary mouse cells to behave like embryonic stem cells. Because this method of stem cell creation avoids the destruction of an embryo, many ethical concerns could potentially be side-stepped. Could this be the answer to the stem cell debate?

What are stem cells?

Most cells in an organism are somatic cells. Somatic cells are differentiated, or specialized, and this enables the different tissues and organs in the body to have different functions. Stem cells, on the other hand, are undifferentiated and have the potential to become many different types of cells. The most versatile type of stem cell is the embryonic stem cell, or ES cell. ES cells are pluripotent, meaning they have the potential to become any type of cell in the body. ES cells are only found in the very early stages of embryonic development. At this stage, the organism is called a blastocyst and consists of a tiny round ball of undifferentiated cells surrounded by cells that will become the supporting placenta.

Personalized stem cells

Ultimately, scientists hope to use stem cells as a method of cell transplantation therapy, in which disease-ravaged cells and tissues in a patient’s body would be replaced by new and healthy counterparts created from stem cells. However, as with organ transplantation, the possibility of rejection is one of many hurdles that need to be cleared before stem cell transplantation therapies are used routinely to treat patients.

The creation of stem cells that are genetically identical to the patient would be an elegant way to solve the problem of rejection of foreign tissue. There are a few methods in development for making such personalized stem cells, but until recently, the method receiving the most press was somatic cell nuclear transfer. In this technique, the genetic material is taken out of a patient’s somatic cell, such as a skin cell, and then injected into an oocyte, or unfertilized egg. If the fusion is successful, the new hybrid cell would develop into a blastocyst, from which the personalized ES cells could be harvested. This method, however, results in the destruction of an embryo, which critics argue is the equivalent of sacrificing a life.

Turning back the clock

Last year, a group at Kyoto University in Japan published the results of a study in which they showed that the introduction of four proteins into mouse skin cells was able to re-program the cells, tricking them into behaving like ES cells. The four proteins belong to a particular class of proteins called transcription factors, which have the ability to enter the nucleus of the cell, where the genetic material, or DNA, is housed. Transcription factors physically interact with DNA and help to control which genes will be activated. This, in turn, determines the action or function of the cell.

The Japanese scientists found that the introduction of four particular transcription factors changed the behavior of the cells and made them act similar to ES cells. They dubbed these cells, induced pluripotent stem cells, or iPS cells. These iPS cells, however, were different from real stem cells in some ways, most significantly in their inability to become every type of tissue in an adult mouse. To many scientists, it seemed far too simple that only four transcription factors were required to turn a somatic cell into a stem cell, and many were skeptical about these surprising results.

Recently though, the team from Kyoto, as well as other scientists working in Los Angeles and Boston, have confirmed and extended these exciting results. Using the same four transcription factors, the scientists have created iPS cells that are indistinguishable in most ways from ES cells. Most importantly, the new iPS cells are able to differentiate into every type of tissue in an adult mouse. These results indicate that these iPS cells have, in fact, been re-programmed to regress into an ES cell-like state.

No embryos were harmed in the making of these cells

Perhaps one of the most exciting things about these results is that iPS cells can be created and grown without the destruction of an embryo. This sidesteps many ethical concerns that have been raised by critics. It also allows research on iPS cells to be conducted using restricted federal funds in the U.S.

It is important to note the independent confirmation of these results by three different groups. Scientific progress relies on the reproducibility of an individual group’s results. Although scientists were initially skeptical about this re-programming technique, there is more confidence in these results now that multiple groups have observed the same thing.

Cautious but hopeful

Scientists hope that in the future human somatic cells can be re-programmed in a similar fashion. One can imagine creating stem cells from a small sample of cells from the skin of a patient. These stem cells could then be induced to differentiate into whatever type of cell was necessary to treat the patient’s disease. Because the re-programmed cells come from the patient’s own body, there is no risk of rejection.

Of course, scientists are careful to caution that any type of cell therapy reliant on iPS cells is still many years away. The technique of re-programming cells, while promising, has yet to be demonstrated using human cells. It is likely that more than four transcription factors will be necessary to effectively re-program the more complex human cell. In addition, two of these transcription factors are well-known proto-oncogenes, meaning they are associated with the development of cancer. In fact, a fifth of the mice that developed from blastocysts containing iPS cells developed cancer that was caused directly by the iPS cells. Because of these potential setbacks, scientists emphasize that it is imperative to continue researching all types of stem cells and all methods of creating stem cells. We still have much to learn about how stem cells work and what makes them so powerful.

–Stephanie Wai, Harvard Medical School

For More Information:

One of many news articles covering iPS cells:
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Primary Literature:

Maherali et al. Directly Reprogrammed Fibroblasts Show Global Epigenetic Remodeling and Widespread Tissue Contribution. Cell Stem Cell 1, 55-70 (July 2007).

Okita et al. Generation of germline-competent induced pluripotent stem cells. Nature advance online publication, 06 June 2007 (doi:10.1038/nature05934).

Takahashi and Yamanaka. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126, 663-676 (August 2006).

Wernig et al. In vitro reprogramming of fibroblasts into a pluripotent ES-cell-like state. Nature advance online publication, 06 June 2007 (doi:10.1038/nature05944).

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