New Stem Cell Technique is "Major Advance"

The development of stem cell science and the cultivation of embryonic stem (ES) cells has been marked by controversy due to the required destruction of the embryos from which the cells derived. Embryonic stem cells are valued because they are undifferentiated cells that, given the right biological prompts, can develop into almost any other type of cell. It is asserted that stem cells can repair the damage from injury, illness, and aging, and even potentially cure a great many human diseases.

In 2006, a major ethical and technological hurdle was surmounted when researchers discovered how to make adult cells “behave” like embryonic ones — thus, no more need to destroy embryos in the process. These “reprogrammed” cells are known as induced pluripotent stem (iPS) cells. Shortly thereafter, researchers figured out how to reprogram adult cells directly into other types of adult cells, skipping the embryonic reversion stage.

However, these too had their limitations. The iPS cells retained copies of the inserted genes (that promoted their change) which made them more prone to tumorogenesis (this outcome can also taint experimental data). There is also some evidence that iPS cells are not exactly the same as ES cells (some researchers suggest that these cells retain a “molecular memory” of their tissue of origin). Further, the method for making iPS cells is very inefficient, as only 1 out of 1000 cells actually becomes pluripotent, and it takes nearly one month for this to occur.

Pluripotent: Embryonic stem cells are able to develop into any type of cell, excepting those of the placenta. Only embryonic stem cells of the morula are totipotent: able to develop into any type of cell, including those of the placenta.

But now comes the big break-through: stem cell researcher Derrick Rossi and colleagues at the Harvard Medical School, in Cambridge, have developed a new technique using synthetic, messenger RNA (mRNA, a class of ribonucleic acid molecules) sequences that correspond to the DNA sequences inserted into cells during reprogramming. The advantage to using RNA is that these macromolecules (which are essential for copying genes) are quickly broken down in the cells, leaving a reprogrammed cell that is “identical” to its mother cell.

There was just one problem. Inserting RNA into cells tended to trigger the cells’ immune response; the cell interpreted the nucleic “Trojan horse” as an invading virus, and began attacking it and destroying it before it could accomplish its mission. In some cases, the immune response led to a type of cellular suicide, known as apoptosis (or programmed cell death), as a final defense.

But with slight modifications to just two of the mRNA molecule’s nucleotides (i.e., 2 of the 4 letters that pair up and code for various amino acids), they were able to manufacture  RNA that the cell would recognize as its own.

After just two weeks of applying daily doses of this synthetic RNA to connective tissue cells called fibroblasts, they found that the cells dedifferentiated, that is, they returned to an embryonic stage. The team has termed these “RiPS” for RNA-induced pluripotent stem cells.

The "life cycle" of an mRNA in a eukaryotic cell. RNA is transcribed in the nucleus; processed, it is transported to the cytoplasm and translated by the ribosome. At the end of its life, the mRNA is degraded. The insertion of "foreign" or artificial RNA (to produce proteins to help repair tissue) can trigger an immune response. In the new technique (RiPS cells), the synthetic RNA's coding is altered, making it acceptable to the host cell's defenses. In this way cells can be stimulated to produce lacking proteins, or replace defective ones.

Not only did this technique cut the reprogramming time in half, but the yield of RiPS cells  increased almost 100 times. So far, it appears that these RiPS cells are a much closer match to their source cells than regular iPS cells.

This technique is sort of the reverse operation of another, fairly new RNA technique known as RNA interference (RNAi), which allows researchers to selectively silence certain genetic instructions.

According to one researcher at the Harvard Stem Cell Institute, this new synthetic RNA technique is a “major advance” for stem cell science.* The researchers plan on exploring ways to use RiPS cells to replace proteins in patients with various genetic disorders.

The research was published recently on the Cell Stem Cell journal website; under the title:  Highly Efficient Reprogramming to Pluripotency and Directed Differentiation of Human Cells with Synthetic Modified mRNA. Additional authors listed for the paper are:

Luigi Warren, Philip D. Manos, Tim Ahfeldt, Yuin-Han Loh, Hu Li, Frank Lau, Wataru Ebina, Pankaj K. Mandal, Zachary D. Smith, Alexander Meissner, George Q. Daley, Andrew S. Brack, James J. Collins, Chad Cowan, and Thorsten M. Schlaeger.

* Douglas Melton, quoted in a news report by Gretchen Vogel (‘New Technique RiPS Open Stem Cell Field’) in the October 8, 2010 edition of Science magazine.

Top image: Human embryonic stem cells in cell culture; public domain

Pluripotent diagram: Mike Jones; C CBY –  SA  2.5

Messenger RNA diagram: Sverdrup; public domain

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